Androgen receptor antagonists a patent review (2008 - 2011)

1.Introduction

2.Patented AR antagonists

3.Conclusions

4.

Expert

opinion

Review

Androgen receptor antagonists:a patent review (2008--2011)

Michael L Mohler,Christopher C Coss,Charles B Duke III,Shivaputra A Patil,Duane D Miller &James T Dalton ?

?

Preclinical Research and Development,GTx,Inc.,Memphis,TN,USA

Introduction:Androgen receptor (AR)antagonists are predominantly used as chemical castration to treat prostate cancer (i.e.,in conjunction with androgen deprivation therapy (ADT)).Unfortunately,castration-resistant prostate cancer (CRPC)typically develops that is refractory to targeted therapy.Insights into CRPC biology have led to the emergence of a promising clinical candidate MDV3100(1)and a resurgence in this field.A pipeline of preclinical competitive 1.1

The androgen receptor as a pharmacological target 1.1.1AR signaling

The androgen receptor (AR)is a member of the nuclear hormone receptor family and functions as a ligand-activated transcription factor in diverse tissues throughout the body [1].The AR shares greatest sequence homology with the progesterone (PR),glucocorticoid (GR),mineralocorticoid (MR)and estrogen (ER)receptors having 80--90%of DNA-binding domain (DBD)amino acid sequence in common but differing in the ligand-binding domain (LBD)by as much as 49%and thus permit-ting differential ligand recognition.Unliganded or apo-AR resides in the cytoplasm bound by heat-shock proteins,held in an inactive state.Accepted models of classic AR action suggest that upon ligand binding,the receptor translocates to the nucleus,homo-dimerizes and binds specific DNA sequences known as androgen response elements (AREs)in the promoter or enhancer region of target genes resulting in changes in gene expression [2].Growing evidence also supports a rapid signaling role for the AR whereby androgen-mediated effects are detected in an amount of time insufficient for de novo RNA synthesis (seconds)[3,4].These non-genomic

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effects include direct interaction with critical intracellular effectors such as phosphoinositide 3-kinase (PI3K)and the tyrosine kinase SRC [5,6].Though ubiquitously expressed,AR signaling is tightly controlled in a temporal and spatial manner by many factors.These include modulation of local ligand concentration and bioactivation,co-regulator expres-sion,chromatin structure and input from numerous kinase signaling cascades [3,7].

1.1.2

Modular nature of the AR

Structurally,the AR is a modular protein made up of discrete functional domains working in concert to affect androgen signaling (Figure 1).The amino-terminal of the AR,or N-terminal domain (NTD),is both necessary and sufficient for AR-mediated transcription [8].The NTD contains several well-characterized transcription co-regulator interac-tion domains that afford its recruitment and stabilization of cellular transcriptional machinery as well as a polymorphic region consisting of variable numbers of the trinucleotide (CAG,coding for glutamine)repeats [3,9].The number of repeats is inversely related to AR activity and associated with a spectrum of androgen insensitivity diseases.The NTD is also known to contact the carboxy-terminal LBD when an agonist is bound,creating intra-and intermolecular AR N --C interactions that play critical roles in both the nuclear shuttling and transcriptional capacity of the receptor [10,11].Critical ‘FxxLF’and ‘WxxLF’motifs in the AR-NTD mimic the ‘LxxLL’nuclear receptor box motif found in many co-regulators,facilitating competition for AF2-binding between AR-NTD and co-regulator elements [12].The highly conserved DBD contains two zinc fingers oriented such that the AR recognizes inverted repeated nucleic acid sequences primarily in the regulatory regions of target genes [13].The

similarity and promiscuity of response elements among related receptors suggest that response elements are minimally involved in signal specificity [3].However,variability in ARE sequence has been shown to dictate critical allosteric interactions such as head-to-head versus head-to-tail homodi-merization [14].Between the DBD and the C-terminal LBD lies the hinge region containing the nuclear localization signal (NLS).The NLS contains two clusters of basic amino acids that permit its interaction with cytoskeletal components upon ligand binding [15].Recently,the hinge region has also been found to serve as an integrator for signals coming from different pathways that provide feedback to the control of AR activity [16].The LBD is the carboxy-terminal domain of the AR and the nexus of androgen signa-ling.When bound to endogenous ligands,conformational changes in the LBD stabilize the ligand --receptor complex via charge-clamp,this in turn facilitates the aforementioned N --C interaction and provides additional co-regulator binding domains [17,18].Whereas the NTD is required for transcrip-tion,several active AR splice variants lacking the LBD have been described [19,20].

1.1.3

AR physiology

Androgen signaling initiates early in fetal development and is responsible for male sexual differentiation.Production of the predominant circulating androgen testosterone (T)is detectable in the 8th week of male embryo development and will ulti-mately rise to adult levels during pubertal development [1].T is primarily produced by the Leydig cells in the testis but is also synthesized in the adrenal cortex,liver and in the female ovary [17].Testosterone can be reduced to the more potent androgen 5a -dihydrotestosterone (DHT)or aromatized to estradiol in a tissue-specific manner depending on the required endocrine signal [21].AR tissue expression is strongly correlated with androgen sensitivity,which is readily apparent in accessory sexual tissues [22].Hershberger et al.performed classical studies whereby male rats were castrated and changes in androgen-dependent tissues monitored.These models,still very much in use today,served to characterize androgen physiology and as a platform to study the effects of exogenous androgen administration [23,24].Androgen withdrawal produces declines in anabolic (muscle and bone mass)and androgenic (size of epididymis,vas deferens and prostate)features.Androgenic processes supported by AR signaling include the development,growth and support of male primary sexual characteristics,as well as exerting influence on secondary gender dimorphic sexual characteristics such as body conformation (bone and muscle mass),skin quality,hair distribution and adipose tissue,while also required for their proper homeostasis regardless of sex [21,25-27].Knockout mouse models suggest critical functions in follicular maturation,female fertility and brain patterning and activation driving sexual behavior as well [27,28].With such critical roles in numerous physiological processes,it follows that dysfunctional androgen signaling is implicated in disease.

Article highlights.

.

The role of the androgen receptor (AR)in prostate

cancers including castration-resistant prostate cancer has been confirmed,spurring resurgence in the field of AR antagonism.

.

Recent AR antagonists have been used to discover novel mechanisms of AR action,providing information-rich screening paradigms and novel design targets.

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C-terminally targeted competitive antagonists are now often screened as nuclear translocation inhibitors,selective AR downregulators or degraders (SARDs),antagonists of wild-type and escape mutant ARs (pan-antagonists),and/or antagonists of AR target organs in vivo .

.

Despite challenges in compound design,N-terminally targeted noncompetitive antagonists with promising preclinical profiles have been reported.

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The advances in AR biology and the emergence of a promising clinical candidate (MDV3100(1))suggest that novel therapeutics targeting the AR are coming.

This box summarizes key points contained in the article.

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1.2

AR-dependent diseases and their preclinical model systems

A variety of diseases have their etiology and/or pathology mediated by the AR.Collectively these diseases are called androgen-dependent diseases.The most pervasive and delete-rious of these diseases affect the prostate.As the male ages,the androgenic effects can become detrimental,promoting the development of benign prostatic hypertrophy (BPH),pre-neoplastic diseases including prostatic intraepithelial neoplasia (PIN)or atypical small acinar proliferation (ASAP)or overt prostate cancer (CaP).Androgens also have a role in gynecologic neoplasias such as breast and ovarian cancers,and disorders such as polycystic ovarian syndrome and precocious puberty.Skin disorders in both sexes such as acne,hirsutism,seborrhea and androgenic alopecia also fall into the category of androgen-dependent disease.In each of these cases,the patient would benefit from AR inhibition.However,current antagonists block activation of the AR in a nonselective manner across all AR-dependent tissues.Thus they produce deleterious antagonism of anabolic AR effects,limiting their use in AR pathophysiological states whose affected population consists of relatively young or healthy patients,for example,acne and baldness.A few selected AR-dependent diseases are discussed in greater detail below,along with preclinical models used to characterize the efficacy of AR antagonists in some of these diseases.1.2.1

Prostate cancer

1.2.1.1Mechanisms conferring castration resistance

The hormonal dependence of prostate cancer was first described in the early 1940s [29].Since that time,the androgen requirements of both the normal and malignant prostate,at least early in its disease course,have been extensively charac-terized [30,31].As such,the mainstay of prostate cancer therapy is androgen ablation by medical or surgical castration with or without a competitive AR antagonist [32].Though androgen

blockade is generally well tolerated and efficacious,tumors initially sensitive to therapy will eventually progress to castration-resistant prostate cancer (CRPC),despite treat-ment,as evidenced by elevations in prostate serum antigen (PSA)or metastasis,usually in less than 2years [33].CRPC is treated primarily with cytotoxic agents,has a poor prognosis and ultimately claims the life of the patient [31,34].Recent FDA approvals for CRPC such as abiraterone and sipuleucel-T are now available but these agents only increase survival times by 3--12months [35].Despite no longer responding to first-line endocrine therapies,several recent studies suggest that the androgen axis is of continued importance in CRPC [36].

Prostate cancer cells adapt to the selective pressure applied by therapy in a number of ways.AR gene amplification has been reported in 22%of CRPC patients though not always leading to increased receptor expression [37].Higher cellular levels of AR can sensitize cells to existing low androgen levels or even elicit a response from weaker endogenous androgens.Likewise,promiscuous AR binding and activation by andro-genic precursors,or other steroidal hormones such as proges-terone,estradiol and even nonsteroidal anti-androgens,have been reported with common gain-of-function mutations in the LBD (e.g.,T877A and W741L)[38].Some CRPCs express a functionally active AR devoid of an LBD,circumventing the need for ligand completely [19,20].Similarly a number of co-activators are expressed at higher levels in CRPC than in treatment-naive prostate cancer and could serve to amplify the constitutive activity of the AR NTD [39].Many of these compensatory mechanisms offer distinct druggable targets and novel therapeutic opportunities.

1.2.1.2

Preclinical models of prostate cancer

Prostate cancer cell lines,reflecting many disease stages,are successfully grown in culture and are important tools in the search for novel prostate cancer therapies (Table 1).Several

Hinge

NH

2

––COOH

1

559624676

NTD

919DBD

LBD

618

NLS 634

AF-1

poly-Q

58–68

88

Y741 T877AF-2

H874NH 2

––COOH

AF-1

AR AR-3

Shortened splice variant exon

V715Figure 1.Schematic depiction of full-length human androgen receptor and the splice variant AR-3reported by Guo et al.(2009).AR-3,expressed in response to hormonal therapy (androgen deprivation),contains activating function-1(AF-1)but lacks the ligand-binding domain of AF-2.

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models carry molecular aberrations of the AR commonly found in the clinic.The T877A LBD mutation present in the LNCaP cell line derived from a lymph node metastasis is a common feature reported across prostate cancer meta-stases and accommodates binding of progesterone and cortisol [40].LBD mutations at amino acid H874are also common and demonstrate altered ligand specificity [38].Both the LAPC4and LNCaP models are routinely employed in the study of androgen-dependent prostate cancer,the principal difference being the expression of wild-type AR (wtAR)in LAPC4cells.CW22-Rv1retains mixed features of androgen responsiveness as it is derived from a human epithelial prostate cancer propagated in mice following castration-induced regression and relapse [41].These cells also express AR splice variants common to CRPCs [19].PC-3and DU145are also of prostate cancer origin but do not express the AR.PC-3but not DU145cells retain the ability to express AR and will do so upon treatment with a demethylating agent 5-aza-2￠-deoxycytidine [42].Both PC-3and DU145cells are commonly utilized in the study of androgen-independent prostate effects.

1.2.2

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS)is the most common endocrine disorder affecting up to 10%of pre-climacteric women and is characterized by luteinizing hormone (LH)hypersecretion,hyperinsulinemia coupled with heightened insulin resistance,hyperandrogenism and compromised ferti-lity [43,44].The molecular underpinnings of this disease are poorly understood but androgen excess,and symptoms thereof,is a cardinal component of PCOS and a common means for diagnosis [44].Exogenous androgen administration in non-PCOS women,such as anabolic steroid use or hormone therapy in transgendered individuals,results in similar ovarian pathology and infertility supporting a critical role for androgens in PCOS [45,46].Anti-androgens are primarily used to ameliorate hirsutism common in PCOS patients but reports exist of anti-androgen administration restoring ovulation in subsets of patients [47-49].It has been suggested that the limited potency of existing anti-androgens prevents their broader efficacy [43].Several animal models have been developed encompassing the myriad symptoms

associated with this complex disease [50].The translational relevance of therapeutic success in any given model is debated as the etiology of PCOS is by definition multifactorial and probably patient dependent.A clearer understanding of the role androgens play in PCOS will probably inform further clinical evaluation of existing anti-androgens and the design of novel therapies.

1.2.3

Epithelial ovarian cancer

Epithelial ovarian cancer is the most lethal gynecological malignancy and many reports suggest the involvement of androgen signaling [51].Primary cultures of ovarian cells demonstrate increased proliferation as well as decreased cell death upon androgen treatment,which corresponds to the expression of the AR in both normal ovarian surface epithe-lium and up to 95%of ovarian cancers [52-55].Studies have also linked pre-diagnostic circulating androgenic precursors and surrogate markers of hyperandrogenism to increased risk of ovarian cancers [56,57].In women with epithelial ovarian cancer,researchers have reported an association between short poly-glutamine tracts in the AR and decreased progression-free and overall survival [58].These associations ultimately led to the evaluation of anti-androgen therapy in two clinical trials,neither of which demonstrated significant improvement in progression-free or overall survival [59,60].Unfortunately,these trials were performed in heavily treated women with refractory disease leaving the efficacy of an anti-androgen as first-line therapy an open question.The study of the role of the AR in ovarian cell maintenance or transformation remains in its infancy when compared with other endocrine cancers but both AR expressing and AR null transformed ovarian cellular systems have been described [61].

1.2.4

Breast cancer

The role of androgens in breast cancer is highly controversial.A history of clinical success in treating breast cancer patients with androgens is balanced with opposing studies refuting asso-ciations between circulating levels of androgens and malignant breast [21,62,63].Though historically treated with agonists,an ongoing clinical trial in selected breast cancer patients (AR positive but negative for ER and PR)is evaluating the efficacy of the anti-androgen bicalutamide [64].The general concept in employing an agonist is supported by an accepted inhibitory role of androgens in normal breast development,anti-proliferative preclinical data,AR expression in a subset of mammary tumors,reduced circulating androgens and andro-genic metabolites in premenopausal women subsequently developing breast cancer and increased risk of disease in women with extended poly-glutamine tracts and reduced androgen sensitivity [62,65-67].Conversely,the use of an antagonist is supported by AR expression in a subset of mammary tumors,anti-proliferative preclinical data,reports of increased circulating androgens in women with breast cancer and studies demonstrating an increased risk of breast cancer in women receiving hormone replacement therapy supplemented with

Table 1.Cell lines commonly used in preclinical models of prostate cancer.

Cell line Androgen responsive AR status

Ref.

LAPC4Yes Wild type

[127]LNCaP Yes T877A mutant [128]CW22-Rv1Yes H874T mutant,Exon 3duplication,

Co-expresses D LBD variant [19,41]

PC-3No not expressed [42]DU145

No

not expressed

[42]

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testosterone [65,68,69].Variable N-terminus and C-terminus directed AR immunohistochemical staining of tumor sections from breast cancer patients suggest that differential AR splicing may contribute to the effects of AR in this disease as well as the controversy surrounding how to target it [70].Several breast cancer cell lines are established research models with many exhibiting androgen dependence and AR expression (Table 2).

2.

Patented AR antagonists

The scope of this review was small molecules reported as AR antagonists appearing in patent documents published in 2008--2011.For the purposes of this review,‘AR antago-nists’that do not bind the AR were excluded.The bulk of this review focuses on androgen-competitive,LBD-directed AR antagonists (Sections 2.1--2.4as outlined below).How-ever,many novel strategies were employed to improve upon traditional LBD-directed anti-androgens,creating a complex heterogeneity in the biological profiles of these agents.In an effort to simplify comparisons between agents,the reviews are segregated according to the type of screening performed.(Due to the aforementioned heterogeneity,assignment of patents to a particular section can be somewhat arbitrary.)Section 2.1discusses anti-androgens that,among other auxiliary mechanisms of anti-androgenicity,inhibit nuclear translocation of AR.Section 2.2discusses selective AR down-regulators or degraders (SARDs)that reduce AR expression at either the transcript or protein level.Section 2.3discusses anti-androgens that were characterized for pan-antagonism (i.e.,targeting multiple mutant ARs in addition to wtAR).Section 2.4discusses agents discovered by screening para-digms relying heavily on in vivo screening in androgen-dependent disease models,rather than relying on mechanistic characterizations of anti-androgenicity.Section 2.5discusses noncompetitive antagonists,that is,those binding to the NTD or blocking interaction(s)with the NTD or the DBD of AR,hence these agents do not compete with LBD ligands for AR binding.This represents a promising and novel strategy for targeting the AR;however,only a few examples have been published thus far,as reviewed infra .

Significant developments in both clinical and basic research have resulted in the development of highly potent second-generation LBD-targeted anti-androgens (Section 2.1--2.4).In the CRPC setting,a counterintuitive brief reduction in serum PSA is often measured following the withdrawal of

bicalutamide or flutamide therapy [71].Though agonism-conferring mutations (i.e.,anti-androgens act as agonists)in the LBD are known for these anti-androgens,the frequency of these aberrations cannot fully explain this phenomenon [72].However,LNCaP cells engineered to overexpress wtAR produce agonist-type responses to bicalutamide treatment.Similarly,AR overexpression is necessary and sufficient to confer anti-androgen resistance in animal models,corroborating that AR amplification detected in a number of CRPCs confers resistance [37,73,74].This anti-androgen resistance in model systems (i.e.,those with elevated AR levels)requires a functional LBD,and the aforementioned AR splice variants lacking an LBD typically require full-length receptor dimerization partners to function [73,75].Taken in concert,these studies suggest that overexpression of full-length receptor is critical in the transition to CRPC and the LBD remains an important target for therapy.Second-generation LBD-targeted anti-androgens such as the clinical leads MDV3100(1)and ARN-509(Figure 2)[41]have been seen as very successful,spurring the discovery of many preclinical LBD-directed and a few novel NTD-directed antagonists by inventors hoping for similar success,as reviewed infra .

2.1

Translocation inhibitors

Recently,two clinical programs targeting the LBD were borne from the same laboratory at the University of California.The two lead compounds,MDV3100(1)[76]and ARN-509(2)(Figure 2)[41,77],differ by only one atom.1was licensed to Medivation,Inc.for commercialization and is in co-development with Astellas Pharma,Inc,including multiple ongoing Phase III trials across an array of prostate cancer patients.2is being developed commercially by Aragon Pharma-ceuticals,Inc.(a start-up company established by an inventor,Dr.Charles Sawyers),which is in a Phase I/II trial for metastatic castration-resistant prostate cancer (mCRPC).

1and 2[77]differ both quantitatively and qualitatively from existing anti-androgens in that they are remarkably more potent than bicalutamide,with binding affinities to the wtAR of only 1.5-to 2-fold reduced from that of DHT compared with 15-fold reduced for bicalutamide (Figure 2)[78,79].The increased potency when combined with comparable pharmacokinetics results in reduced efficacious doses and probably a larger thera-peutic window.Importantly,both ligands remain antagonists in models of CRPC overexpressing AR and 1successfully antag-onizes the W741C mutant,which converts bicalutamide to an agonist [79].The mechanistic explanation put forth for these improved activities by the discoverers of the ligands is based on differences in nuclear translocation of the ligand-bound complex.Bicalutamide-bound AR translocates to the nucleus and interacts with regulatory regions of AR target genes but forms unproductive transcriptional complexes,recruiting mainly co-repressors.In the context of CRPC,where AR and/or co-activators are often elevated,the co-repressor pool is insuffi-cient and aberrant recruitment of co-activators occurs followed

Table 2.Cells lines used in preclinical breast cancer models.

Cell line

Notes

Ref.

T47D

Human;AR(+),ER(+),PR(+)[129]Shionogi Carcinoma Cells (SC115)Murine;Androgen dependent [130]MCF-7

Human;AR(+),ER(+),PR(+)

[131]

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by target gene activation [30,79].1and 2circumvent this problem by severely limiting nuclear translocation in the first place [78,79].2.1.1

Regents of the University of

California --diphenylthiohydantoins as second-generation anti-androgens (MDV3100(1)and ARN-509(2))

Sawyers et al.in WO06124118[76]reported the synthesis of a series of diarylhydantoins [80]as in vivo antitumor agents in models of hormone-refractory prostate cancer.This series conserved the p -CN,m -CF 3phenyl ring of the first-generation anti-androgens (Figure 3)but explored a wide variety of para substituents (R 3)of the other phenyl ring,with or without m-halogenation (R 2),and mostly in the con-text of dimethyl-or cycloalkyl-(mostly cyclobutyl-)(R 1/R 1￠)thiohydantoins as linkers.WO06124118discusses that AR overexpression in LNCaP cells (LNCaP-AR)is sufficient to convert hormone sensitive to hormone-refractory/anti-androgen-resistant prostate cancer [73].Prior art mono-aryl hydantoin anti-androgens [81]displayed agonist activities in this context in vitro (AR reporter systems,R1881-stimulated PSA expression and LNCaP-AR cell growth).Whereas the diarylhydantoins maintained antagonism in vitro (same assays as above)and in vivo (xenografts).Specifically,3(Figure 3)dosed orally (1mg/kg/day)dose dependently inhibited the growth of LNCaP-AR and LAPC4xenografts,whereas bica-lutamide (same dose)did not.1(10and 50mg/kg/day orally)caused LNCaP-AR xenograft regression in contrast to mild growth inhibition for bicalutamide at the same dose,and 1exhibited superior in vivo pharmacokinetics in 8-week-old

FVB mice.Correspondingly,1was selected for further investigation and has now progressed to Phase III clinical trials.Moreover,4--5(Figure 3)also demonstrated nanomolar inhibition of LNCaP-AR cell growth,whereas 6did not.Jung et al.in WO09055053[82]reported the synthesis of diaryl thiohydantoins of general structure 7(R 1and R 2are alkyl or can be fused to form a ring)in which the p -B-ring position is a terminally substituted alkyl group.The applica-tion discusses a similar set of assays but in present tense (i.e.,hypothetically),and no biological data are reported.Although not stated as such,this application may serve a defensive role for protecting https://www.doczj.com/doc/fa9105297.html,pounds 8--10are shown as representative examples in Figure 3.

Jung et al.in WO07126765[77]reported the synthesis of a series of 3-pyridino variants of the template above and charac-terized 2(ARN-509)as being an orally efficacious agent in hormone-resistant prostate cancer xenografts.2,11and bicalu-tamide (at 100nM,respectively)completely suppressed R1881-induced PSA expression in LNCaP (hormone-sensitive)cells and inhibited the growth of these cells.Further,2and 11but not bicalutamide (up to 1μM)suppressed PSA in LNCaP-AR (hormone-resistant)cells.2(10mg/kg/day orally)caused tumor regression in LNCaP-AR xenografts,suggesting it may be able to treat CRPC.Ouerfelli et al.in WO08119015[83]disclosed the large-scale synthesis of 2.

2.1.2

Aragon pharmaceuticals --diarylthiohydantoins as AR antagonists in vitro

Smith et al.in WO11103202[84]reported the synthesis of ~300thiohydantoins whose structure varied mostly in the

NC

F 3C

N

N

S O

N H

F

O

1 MDV3100

N

NC

F 3C

N

N

S

O

N H

F

O

2 ARN-509

O 2N

F 3C

N

NH

O

O

NC

F 3C

N H

O

S O 2

OH

F

Bicalutamide Nilutamide

First generation anti-androgens

Second generation anti-androgens

Figure 2.First-and second-generation anti-androgens.

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identity of the aromatic A-ring and substitution patterns,as depicted in general formula 12(Figure 3).The thiohydantoin moiety was conserved throughout,typically substituted with a spiro-cyclobutane ring.The A-ring system was mostly 4-cyano-3-trifluoromethyl (or 3-methyl)phenyl but sometimes included a hetero atom (e.g.,3-pyridino)or was a fused bicyclic.The B-ring was frequently substituted with halogens and the para position often incorporated bulky side chains.Each com-pound was tested in agonist and antagonist mode in an in vitro transcriptional activation assay and reported qualitatively (ago-nist if value was 20?higher than DMSO control;antagonist if IC 50<1μM),revealing that the majority of compounds pos-sessed some antagonism and far fewer possessed agonism.Other assays were discussed but with no (or limited)data reported.

2.2

Selective AR downregulators or degraders

Several groups now have characterized their LBD-directed ligands for their ability to selectively downregulate (mRNA levels lowered)and/or degrade (protein concentration lowered)

the AR,discussed collectively as SARDs for this review.For instance,Njar et al.in WO08076918characterized a panel of compounds with SARD activity in micromolar range (see 13--17in Figure 4).Although very little of the SARD literature is peer-reviewed,several groups report data of this type in the patent literature.Recent reports indicate the impor-tance of AR activity in the vast majority of prostate cancers,even if they are no longer hormone sensitive.Consequently,potent SARDs theoretically should work in hormone-sensitive and castration-resistant prostate cancer.Thus far,SARD activity has required high concentrations relative to other mechanisms of anti-androgenic action.

2.2.1

University of Maryland,Baltimore --abiraterone (18)analogs (lyase inhibitors)with SARD and antitumor activity

Njar et al.in WO09114658[85]reported SARD activity in their template of previously disclosed lyase/AR co-inhibitors.

cmpd R 1/R 1′R 2R 3

LNCaP-AR IC 50(nM)

13456

cyclobutyl cyclobutyl

cyclobutyl cyclobutyl F –C(O)NHMe

nt –(CH 2)3CONHMe

92Me

124Me

125H H H

B-ring is replaced with Me

Regents of the University of California: WO06124118

diphenylthiohydantoins as second generation anti-androgens (MDV3100 (1))

cmpd

R 1/R 2R 3R 4/R 11/R 12

8di-Me 9cyclobutyl 10

cyclobuty

H

H H Regents of the University of California: WO09055053diphenylthiohydantoins – hypothetical examples

NC

F 3C

N

N

S

O R 3

R 1

R 1′

R 2

NC

F 3C

N

N

S

O R 1R 2

R 4

R 3

R 11

R 12A

B 7

di-Me none

imidazol-2-yl

CONHMe CN Figure 3.Selected translocation inhibitors.

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F o r p e r s o n a l u s e o n l y .

Their lead compound 19(Figure 5)demonstrated lyase (cyto-chrome P450monooxygenase 17a -hydroxylase/17,20-lyase (CYP17))inhibition of 300nM and significant AR-binding affinities (IC 50values)in wtAR (405nM (compared with 22nM for DHT and 4,300for bicalutamide for wtAR),T877A (845nM)and T575A (454nM),whereas the known lyase inhibitor abiraterone (18)did not bind AR.Bicaluta-mide and 19demonstrated full (90--99%)AR antagonism of wtAR and T877A AR-mediated transcriptional activation at 10μM.19at 1,5,10and 15μM was able to dose-dependently decrease AR levels in LNCaP cells.In LAPC4(wtAR)cells in vitro ,19(15μM)reduced AR protein expres-sion by 89%,20at 15μM (Figure 5)reduced expression by 90%and SARD activity was also seen in vivo in the LAPC4xenografts (discussed infra ).In comparison,bicaluta-mide did not demonstrate any SARD activity.The SARD activity of 19was at least partially due to destabilization of the protein,but the proteolytic pathway was not specified.19(0.13mmol/kg injected subcutaneously twice daily)prevented tumor formation in LAPC4xenografts (6.9vs 2410.3mm 3in control group on day 86)that was

more potent than bicalutamide alone or castration alone.Fur-ther,19(presumably same dose)in established tumors caused regression to a significantly greater degree than bicalutamide or castration.

Njar et al.in W009120565[86]reported the synthesis of a series of 19analogs as putative prodrugs.19demonstrated LAPC4xenograft efficacy (as discussed supra ),but unfortu-nately had <10%oral bioavailability in rats.The 3-OH group was substituted by esters linked to sulfonamides (21),amino acids (22--23),organic acids (24),phosphates (not shown)and so on,with the intention of attaining oral bioavailability (Figure 5).However,the experimental results disclosed in the examples section did not evaluate these com-pounds as prodrugs,but rather focused on further characteri-zations of 19.Similar putative prodrugs of 19(and 18)were reported by D.Casebier of Tokai Pharmaceuticals in WO10091306[87].In these agents,the X group protecting the 3-hydroxyl was various carbonyl functionalities containing aryl,alkyl,arylalkyl,alkoxyalkyl and/or charged side chains (not shown).Again,these were not characterized as prodrugs in the examples.

Vitamin E succinate (17)

EC 50 = 38 μM

O

O

O

HO

O

O HO OH

OH

OH

OH

O

HO OH

OH

OH

OH

O

H N

HO

O

CF 3

H 3CO

HO O

O

OCH 3

OH

(-) epicatechin (13)EC 50 = 13 μM

Quercetin (14)EC 50 = 25 μM Flufenamic acid (15)EC 50 = 100–200 μM

Curcumin (16)EC 50 = 35 μM

Figure 4.Representative selective androgen receptor downregulators (SARDs).

M.L.Mohler et al .

548

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n 01/14/13F o r p e r s o n a l u s e o n l y .

University of Maryland, Baltimore: WO09114658

abiraterone (18) analogs (lyase inhibitors) with SARD and anti-tumor activity, and prodrugs thereof

Hydroxyflutamide

AstraZeneca: WO08044033

hydroxyflutamide analogs as SARDs

AstraZeneca: WO09081197

bicyclo(hetero)aromatics SARDs

Ligand Pharmaceuticals, Inc.: WO08124000thiazole amides

Androscience Corporation: WO09017815

curcumin (16) analogs as SARDs and in vivo antagonists (hair growth, prostate xenografts)

O 2N

F 3C

N H

O OH

R

F 3C

N H

O

OH

(aliphatic side chain)

1

3

N

X

2

N

N

R 4

(R 5N

HO

N

N N

N F 3C

N

27

35

N H

O

N

S

H 3CO

S O 2

34

N

H

O

N

S

N

S O 2

R 1

R 2O OH

R 1

R 2

R 3

N

N

N N

N F 3C

O

N

N 26

cmpd R side chain pIC 50 (SARD)28 CN –(CH 2)10S(CH 2)3CF 2CF 3 6.30129 CN –(CH 2)10SO 2(CH 2)5CH 3 5.79230 CN –(CH 2)10SO 2(CH 2)2CF 2CF 2CF 3 5.80531 CN –(CH 2)10SO 2(CH 2)3CF 2CF 3 6.24532 CN –(CH2)6SO(CH 2)3CF 2CF 3 6.45033 NO 2 –(CH 2)9S(CH 2)3CF 2CF 3 6.073

cmpd R 1 R 2 R 3 linker 16

OH OMe H diketone 36 OMe OMe H

enol 37

OMe

OH

CH 2CH 2COOEt

enol

Figure 5.Patented selective androgen receptor downregulators or degraders (SARDs).

Androgen receptor antagonists:a patent review (2008--2011)

Expert Opin.Ther.Patents (2012)22(5)

549

E x p e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a r y o n 01/14/13

F o r p e r s o n a l u s e o n l y .

2.2.2

AstraZeneca --bicyclo(hetero)aromatics SARDs

Bradbury et al.in WO09081197[88]reported the synthesis of more than 800heterobicyclic compounds capable of inducing cellular downregulation of the AR.The generic composition of matter included compounds with ?3nitrogen atoms in a [3.4]bicyclic moiety and substitution as illustrated in general structure 25(Figure 5)of the application,where X 1--X 3are N or C and the A-ring is a substituted hetero-or carbocyclic group.The selected examples were [1,2,4]triazolo[4,3-b ]pyri-dazines.Each compound was tested in an LNCaP AR downregulation assay,revealing average IC 50values from the ~500nM to mid-μM.One of the more potent compounds 26had a SARD IC 50value of 0.24μM and AR binding (LanthaScreen ?)of 1.3μM.By comparison,27demon-strated 10and >100μM values in the AR downregulation and binding assays,respectively,possibly suggesting that potent downregulation requires AR binding.Although AR binding and AR downregulation were reported,no other in vitro or in vivo anti-androgenic activity was demonstrated.

2.2.3

AstraZeneca --hydroxyflutamide analogs as SARDs

Bradbury and Hales in WO08044033[89]reported the synthesis of a series of compounds that shared the substituted aniline and tertiary alcohol groups of bicalutamide but the sulfonylphenyl group was replaced with a variety of linear aliphatic groups of ~12--18atoms length,typically with a sulfide,sulfoxide or sulfone linker located ~4--8atoms from the end of the aliphatic chain.Often,the methylene/methyl groups near the end of the aliphatic chain were per-fluorinated.pIC 50values of >5(<10μM)was reported for many (~100)of these compounds in AR downregulation assays,with the most potent being 28--33(Figure 5)with a pIC 50range of 5.8--6.5.

2.2.4

Ligand Pharmaceuticals,Inc.--thiazole amides

Zhi et al.in WO08124000[90]reported the synthesis and in vitro %antagonism (DHT-mediated transcriptional activa-tion)of a series of thiazoles.Although hundreds of fully effi-cacious (at 10μM)compounds were tested,the lack of dose response data makes it impossible to understand SAR patterns and potency compared with known antagonists,nor are these compounds classifiable as selective androgen receptor modu-lators (SARMs)versus pure antagonists.Although the abstract and embodiments purport that these compounds can reduce the number of ARs in a cell (i.e.,SARDs),the authors could not find any data to support this assertion.34and 35are given as representative examples (Figure 5).

2.2.5

Androscience Corp.--Curcumin (16)analogs as SARDs and in vivo antagonists (hair growth,prostate xenografts)

Shih et al.in WO09017815[91]published methods of treating skin disorders and hair loss with their lead anti-androgens 36

and 37(Figure 5).The curcumin analogs varied mostly in the side chain in the middle of the linker,but also had variable linker conjugation and catechol methylation patterns.The anti-androgenicity of a panel of curcumin analogs was reported as their ability to enhance AR degradation in LNCaP cells following a 48-h incubation with the SARD,as shown in western blots.The most potent compounds reported had approximate IC 50values of 1μM (reported qualitatively).Further they demonstrated that the receptor degradation in LNCaP and T47D cells was selective to AR and not other nuclear hormone receptors such as PPAR,RXR,ER,PR nor was it induced by known anti-androgens,finasteride,hydroxy-flutamide and cyproterone acetate.Anti-androgenicity was demonstrated by 36,which inhibited LNCaP cell growth at 5μM in the presence or absence of DHT.Claimed are compo-sitions of a SARD in combination with known dermatologic products.The detrimental dermatologic effects of androgens are well appreciated but conventional anti-androgens are not generally used due to systemic side effects.36was characterized in a panel of in vivo assays to induce sebaceous gland regression and reduce seborrhea,as well as overcome testosterone-induced hair growth suppression.It was also active in a model of Kennedy’s disease in which a polyglutamine (Q49)AR was transfected into COS-1cells.36reduced the development of inactive AR inclusion bodies,suggesting SARD activity in this model.Further 36demonstrated potential as an anti-prostate cancer agent in LNCaP xenografts and hastened wound healing in mice.

2.2.6

STC.UNM --vitamin E (38)analog (39)as a SARD

Thompson et al.in WO08060949[92]reported low potency suppression of AR levels at the mRNA and protein levels for vitamin E (38)and several metabolites thereof.38at >30μM slightly inhibited LAPC4cell growth whereas its major oxidation product,a -tocopherylquinone (39),demon-strated significant growth inhibition at 10--40μM (Figure 6).39(Figure 6)at 40μM also significantly reduced R1881-induced androgen-sensitive promoter activity (e.g.,fourfold decrease in PSA release)in LNCaP cells.Further,39reduced AR protein (fourfold)and mRNA levels (twofold)in LNCaP (30μM)and LAPC4(25μM)cells whereas 38did not.

2.2.7

Dong (unassigned)--phenoxy-ethylsulfanyl-pyridin-4-one (40)

Dong et al.in US20080015207[93]claimed a method of use of 40(Figure 6),a simple diaryl alkanol for treating AR-dependent diseases such as prostate cancer.40is characterized as being devoid of agonist activities on reporter gene con-structs and cell growth (LNCaP)but 40partially induced and enhanced DHT-induced AR nuclear localization.40demonstrated a variety of anti-androgenic properties at low-to mid-μM concentrations.Said anti-androgenic properties include inhibition of DHT-induced LNCaP (T877A),LAPC-4(wt)and CW22-Rv1(H874Y)cell growth

M.L.Mohler et al .

550

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F o r p e r s o n a l u s e o n l y

.

(<10μM),PSA suppression (5μM),HSP70downregulation (protein required for proper folding of AR (and other pro-teins))in an AR-dependent manner,destabilization of AR in prostate cancer cell lines at mRNA and protein levels,and N-to C-terminal interaction.No in vivo or pharmacokinetic results are reported.

2.2.8

University of Maryland,

Baltimore --diphenylsulfonamides as potent LNCaP anti-proliferative agents

Njar et al.in WO08076918[94]reported the synthesis of several diarylsulfonamides as potent LNCaP anti-proliferative agents.Seventeen compounds from the Catalyst/Maybridge 2003(59,652compounds)and NCI databases (238,819compounds)matching an AR-downregulating agent (ARDA)pharmacophore were selected and tested,producing six active ARDA compounds with EC 50values of 17.5--212μM.The diarylsulfonamide 41(EC 50value of 76μM)was chosen as the lead for optimization based on its ease of modification.Despite being designed as an ARDA,several novel sulfona-mides demonstrated potent LNCaP growth inhibition,with 42,43and 44(Figure 6)having GI 50values of 2.95,2.34and 1.45nM,respectively,without proven ARDA activity (42and 43not tested for ARDA,and 150μM ARDA for 44).43and 44demonstrated competitive binding to the AR in the low-μM range and demonstrated pure AR antagonism in transcriptional activation studies.This suggests that AR antagonism,and not ARDA activity,was the basis

for the potent LNCaP anti-proliferative activity,but does not exclude other targets as well since PC-3(AR-independent)anti-proliferation in the low-μM range was also seen for some of these compounds.These bear some structural resemblance to NTD blockers reviewed in Section 2.5,suggesting that this may be a possible mechanism explaining the high LNCaP potency.

2.3

Pan-antagonism

Genetic mutations to the AR loci increase in frequency from early prostate tumors (<4%),advanced recurrent tumors (10--20%)and prostate cancer bone metastasis (up to 50%)[38,95,96].The increased frequency of detection in advanced disease,coupled with the ligand promiscuity pro-vided by many of the lesions,suggests they are relevant in the transition to CRPC.Many of the most commonly described and well-characterized point mutants are located in the LBD (V715M,W741C,H874Y,T877A,S)and can convert antagonists (hydroxyflutamide,bicalutamide)into weak agonists therefore providing a growth advantage relative to cancer cells harboring wtAR [72,96].The search for compe-titive antagonists that efficiently antagonize these resistance-conferring mutations would provide a viable second-line hormonal therapy option or perhaps even a first-line opportu-nity.Though many of these mutations are described in the context of transformed cell lines grown in culture,most researchers employ reconstituted systems whereby activity against engineered mutant ARs is evaluated in terms of both

O

HO O

O

38

HO

39

STC.UNM: WO08060949

vitamin E (38) analog (39) as a SARD Dong (unassigned): US20080015207phenoxy-ethylsulfanyl-pyridin-4-one (40)

N H

H 2N

S

O

O

NH O 2S

R H 3C

2

R 1

40

University of Maryland, Baltimore: WO08076918

diphenylsulfonamides as potent LNCaP anti-proliferative agents cmpd

R 1

R 2 ARDA (EC 50(μM)) LNCaP (GI 50(nM))41 NO 2 Me 76 n.t.42 NO 2 H n.t. 2.9543 NO 2 F n.t. 2.3444 H

Me

150

1.45

Figure 6.Patented selective androgen receptor downregulators and degraders (SARDs).

Androgen receptor antagonists:a patent review (2008--2011)

Expert Opin.Ther.Patents (2012)22(5)

551

E x p e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a r y o n 01/14

/13F o r p e r s o n a l u s e o n l y .

binding and transcriptional activation.These types of assays provide high-resolution data affording useful comparisons among closely related molecules.

2.3.1

University of Delaware --propanamides with

biaryl B-rings as pan-antagonists,SARD,translocation inhibitor and anti-prostatic in vivo

Koh et al.in US2010331418[97]reported several bicalutamide derivatives in which the B-ring (i.e.,same side as the sulfone)is replaced with various biaryl groups such as biphenyl and naph-thyl.The expanded B-ring was designed to sterically clash with the H12of wtAR,as well as the mutants described below,and hence provide a basis for pan-antagonism [98].The lead compound 45(Figure 7)was characterized as a μM-range pan-antagonist of wt (IC 50=3.5μM),T877A (IC 50=4.5μM),W741C (IC 50=5.9μM)and W741L (IC 50=12.2μM)ARs in in vitro transcriptional assays and lacked AR agonism in all these contexts.45also bound to wt (IC 50=3.0μM),T877A (IC 50=4.1μM)and W741C (IC 50=7.3μM)ARs.45or 46(Figure 7)at 100μM prevented nuclear localization of GFP-AR (green fluorescent protein-tagged AR)when treated with 10μM DHT,whereas DHT or bicalutamide alone induced this activity.45or 46at 50μM reduced AR protein lev-els to ~60and ~35%of untreated,respectively,in LNCaP.In CW22-Rv1cells,45or 46at 100μM reduced protein levels to ~65%.46administered (25mg/kg/day intraperitoneally)to C57BI/6mice demonstrated increased prostate apoptosis in vivo upon quantitative microscopic analysis.

Separately,naphthyl (and biaryl)B-ring compounds such as 47(Figure 7)were reported in WO08013791[99]as μM-range pan-antagonists in vitro .47demonstrated pan-antagonism of wt (IC 50= 3.8μM),T877A (IC 50=9.7μM),W741C (IC 50=3.3μM)and W741L (IC 50=6.0μM)ARs in in vitro transcriptional assays and lacked AR agonism in all these contexts.

2.3.2

Takeda Pharmaceuticals --pyrrolidines as pan-antagonists in vitro

Ito et al.in WO09131196[100]reported finding a series of pan-antagonist pyrrolidine derivatives.Structures 48--53(Figure 7)showed at least 88%binding inhibition in wtAR and LNCaP (T877A)cells (1μM vs 3nM radiolabeled mibo-lerone).51and 52showed 100%inhibition of PSA produc-tion in LNCaP-FGC cells (1μM compound with 0.1ng/ml testosterone)compared with cells incubated with testosterone alone.Bicalutamide,comparatively,inhibited only 75%of PSA production in the same conditions.48--50,52and 53at 1μM (in the presence of 0.1μM DHT)inhibited AR-mediated transcription by more than 80%in COS-7(transfected with W741C AR)cells.

2.3.3

Takeda Pharmaceuticals --pyrazoles as pan-antagonists in vitro

Ito et al.disclosed in WO09028543[101]N-1and C-4substi-tuted pyrazoles as antagonists of wild type as well as mutated

AR (i.e.,pan-antagonists).Several of these pyrazole analogs showed %AR binding inhibition (3nM radiolabeled mibo-lerone)at 1μM of >70%for wild-type and LNCaP (T877A)AR.For example,54(Figure 7)inhibited the binding to wtAR and T877A by 88and 80%,respectively,compared with 94and 88%,respectively,for bicalutamide.The pyrazoles also demonstrate strong PSA suppressive activity.55and 56(Figure 7)suppressed PSA production in LNCaP-FGC cells by 109and 110.2%,respectively,when compared with the testosterone non-addition group,whereas bicalutamide suppressed PSA production only by 75%.Further 55showed 92%inhibition of transcription driven by the mutant AR (W741C),but none of the above demonstrated high efficacy across all assays tested.From the activities reported,55and 58(Figure 7)most closely approximate a pan-antagonist profile,albeit at <100%efficacy at 1μM,sug-gesting that the potency of this template may not be sufficient to pursue clinically.

Separately,Ito et al.continued their work on pyrazoles in WO09119880[102]to find pan-antagonists.The main structural modification of the application was the reversal of the positions of the substituted-4-cyanophenyl (now at N-1position of the pyrazole)and the phenylmethyl (now at C-4)groups.The C-4position was varied to generate the large number of compounds (467analogs).59(Figure 7)inhibited the binding of mibolerone to wtAR and T877A (LNCaP)by 87and 92%at 1μM and was the only com-pound to display high-efficacy transcription inhibition (93%;next closest was 60with 71%;Figure 7)at 1μM against W741C AR.61(Figure 7)showed the strongest reported inhi-bition of PSA production in LNCaP cells (117%)but rela-tively weak efficacy at 1μM in binding and transcription inhibition assays.

The Takeda program (Sections 2.3.2and 2.3.3)presented data consistent with pan-antagonism including the in vitro binding (wt and W741L)and anti-androgenic transcription (W741C)and PSA expression (T877A (LNCaP cells))effects.However,these data were all reported at 1μM and without dose --response data leaving the potency of the pan-antagonism uncertain.So even if an inhibitor was 100%for all of the above,that is,an optimal pan-antagonist profile in this set of assays,it is hard to predict whether these com-pounds would be better than traditional anti-androgens in vivo or in the clinic.

2.3.4

Consiglio Nazionale Delle Ricerche and Istituto Scientifico Romagnolo --R-bicalutamide (62)analogs as mixed antagonists in vitro with weak CW22-Rv1xenograft activity

Varchi et al.in WO10092546[103]reported several propana-mides (63--66),hydantoins (67)and thiohydantoins (68)as R-bicalutamide (62)analogs in which the tertiary alcohol has been replaced with a substituted amino group (Figure 8).These compounds demonstrated cell growth inhibition in

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E x p e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a r y o n 01/14/13

F o r p e r s o n a l u s e o n l y

.

O

N H O 2S

HO

F 3C

NC

47

NC

R 2

N

H 3C

R 3

R 4 for cmpds.48 – 49

for cmpds.50 – 53 O

O

H 31

Takeda Pharmaceuticals: WO09131196pyrrolidines as pan-antagonists in vitro

Takeda Pharmaceuticals: WO09028543pyrazoles as pan-antagonists in vitro

R cmpd R

59

87 92 101 93

60

82 90 109 71

6147 51 117 23Takeda Pharmaceuticals: WO09119880

(reverse) pyrazoles as pan-antagonists

in vitro

2

N

OH

O

N H

HO

F 3C

NC

S

O O

46

University of Delaware: US2010331418

propanamides with biaryl B-rings as pan-antagonists, SARD, translocation inhibitor, and anti-prostatic in vivo

N H

O

NC

F 3C

OH

S O 2

O N

45

H C-4

WO0801379

A

B

binding (%inh) wtAR T877A Tc (%inh)W741C

PSA (%inh) cmpd

R 1

R 2 Q wtART T877A (%inh) W741C

54 H –CONH 2

CH 88 80 107.2 19

55 –CONH 2 F

C 78 68 101.8 92 56 absent –CONH 2 N 66 75 109.0 32 57 absent –CONHCH 3 N 49 79 110.2 38 58 absent –CONH N 70 73 106.1 72

binding (%inh)PSA Tc (%inh)

c mpd

R 1

R 2

R 3

R 4 wtAR T877A W741C

48 (3R )-SO 3CH 3 n.a.

n.a. n.a. 94 97 82

49 (3R )-N 3 n.a. n.a. n.a. 98 97 8550 n.a. Cl OH (3R )-p -carboxamido-phenyl 99 92 98 51 n.a. H OH (3R )-6-bromopyridin-3-yl 21 46 30

52 n.a. Cl (3R )-NHSO 2CH 2-4-F-Ph H

95 63 7353 n.a. Cl (3S )-NHCONH-4-F-Ph H 96 88 89binding (%inh)Tc (%inh)

Figure 7.Patented pan-antagonists of wild-type and mutant androgen receptor (AR).

Androgen receptor antagonists:a patent review (2008--2011)

Expert Opin.Ther.Patents (2012)22(5)

553

E x p e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a r y o n 01/14/13

F o r p e r s o n a l u s e o n l y .

LNCaP (but not DU145and PC-3indicating AR-mediated effects),which is comparable with 62(μM range).63,66and 68but not 62induced apoptosis at 20μM in LNCaP and LNCaP-AR (transfected with AR)cells.Transcriptional activation studies indicated that these compounds are AR antagonists that compete with R1881for activation of the AR at 10μM;however,many also contain some intrinsic agonism at lower concentrations.

Separately,Varchi et al.in WO10116342[104]reported propanamides 69--72(Figure 8)in which the tertiary alcohol of 62was retained and various aryl side chains were appended to the methyl group of 62.These compounds were also analyzed in the assays above with similar μM-range potencies but purported advantages to 62with regard to inducing apoptosis.71dosed at 100mg/kg orally demonstrated anti-tumor activity,which was reported as superior to 62against human CW22-Rv1prostatic carcinoma xenograft,with no signs of general toxicity reported.

2.4

In vivo screened LBD-directed AR antagonists 2.4.1Bristol-Myers Squibb Co.--fused-tetra(hetero)

cycles as potent wtAR antagonists in vitro and in vivo

Norris et al.in WO09003077[105]reported the synthesis of epoxypyrano-isoindolinones such as 73--77(Figure 9)as antagonists of DHT-mediated transcriptional activation in vitro and androgenic organ weight in vivo when dosed

orally at 3mg/kg for 4days.The minimally decorated ana-log 73possessed significant AR antagonism (IC 50=42nM)and inhibited seminal vesicle growth in vivo (46%of intact control),indicating substantial anti-androgenic potential.Adding a methoxyimino tail as in 74marginally increased anti-androgenic activity (31nM,37%of intact control),whereas adding a sulfonamide in this position maintained (75(46nM,not reported))or decreased (76(335nM,42%of intact control))anti-androgenicity.Further,moving the substitution site was tolerated for 77(45nM,35%of intact control).

2.4.2

Bristol-Myers Squibb Co.--fused-tri(hetero)cycles as AR antagonists in vitro

Shan et al.in WO09059077[106]reported the synthesis of epoxy-benzoisothiazoles such as 78--81(Figure 9)as antago-nists of DHT-mediated transcriptional activation in vitro .In this invention,the tetracyclic system of WO09003077(reviewed supra )was simplified to a tricyclic system.In some cases,this resulted in tight binding (10--23nM for examples shown here (data not shown))AR ligands with reduced (100nM range)AR antagonism in vitro .Saturation of the core template appears important for anti-androgenicity (compare 78(1420nM)and 79(198nM)),and substitution of the core only marginally improved in vitro activity (144and 141nM for 80and 81,respectively).

Consiglio Nazionale Delle Ricerche and Istituto Scientifico Romagnolo: WO10092546bicalutamide analogs as mixed antagonists in vitro

NC

F 3C N H

O S O 2

F

R 2

R 1

NC

F 3C

N

O X

F

NH

Q

R 3

Consiglio Nazionale Delle Ricerche and Istituto Scientifico Romagnolo: WO10116342

bicalutamide analogs as mixed antagonists in vitro with weak CW22-Rv1 xenograft activity NC

F 3C

N H

O S O 2

F

OH

R

cmpd chirality

R

69 R Ph 70 R 4-CF 3-Ph 71 R thiophen-2-yl 72 R α-naphthyl

cmpd chirality R 1 R 262 R H OH 63 R Ph NH 264 R Ph –NHSO 2Me 65 S H –NHSO 2C(CH 3)366 S H –NHSO 2(p -CH 3-Ph)

cmpd chirality Q R 3 X 67 S O M e SO 268 R S Ph bond

Figure 8.Patented pan-antagonists of wild type and mutant androgen receptor (AR).

M.L.Mohler et al .

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E x p e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a

r y o n 01/14/13

F o r p e r s o n a l u s e o n l y .

2.4.3

Endorecherche,Inc.--Steroidal (pure)antagonists

of wtAR in vivo and Shionogi cells in vitro

Labrie et al.in WO08124922[107]reported the synthesis and biological testing of 17a -substituted estratriene steroids.These compounds bound tightly to the AR with smaller substituents at the 3or 17a positions favoring pure anti-androgenicity.Conversely,substitution at 3,4,11b ,16and 17a positions favored SARM or pure androgen activity.These compounds acted as anti-androgens in that they reversed the 0.3nM DHT-induced cell proliferation in Shionogi mouse mammary carcinoma cells (SC115cells),as well as in vivo anti-androgenicity on ventral prostate (VP)and seminal vesicles (SV).Cell proliferation IC 50values ranged from 0.35to 24nM while the IC 50of hydroxyflutamide and bicalutamide was 16.8and 48nM,respectively.Thus,the IC 50values of

the 82(0.9nM)and 83(2.5nM)were respectively 12and 5.5times more potent than the IC 50of hydroxyflutamide.Most importantly,none of the compounds had any activity on the basal level of Shionogi cell proliferation,thus indicating their pure anti-androgenic activity.The major interest of these compounds was that they showed a potent and pure anti-androgenic activity in vivo in castrated male rats.82dosed orally (0.1mg per rat)demonstrated no intrinsic agonist activity in VP and SV but reversed DHT-mediated VP and SV growth,an effect requiring 0.5mg of flutamide.

2.4.4

Tong (unassigned)--thioimidazolidinones as hair growth antagonists in vivo

Tong in WO11029392[108]reported novel substituted thioimi-dazolidinones 84--87(Figure 9)AR antagonists (IC 50<1μM)

NC

R 1

N N S O

R 5

R 3

R 3′

R 4

R 2

Tong (unassigned): WO11029392

thioimidazolidinones as hair growth antagonists in vivo

Bristol-Myers Squibb: WO09003077

fused-tetra(hetero)cycles as potent wtAR antagonists in vitro and in vivo Bristol-Myers Squibb: WO09059077

fused-tri(hetero)cycles as AR antagonists in vitro

F 3C

NC

2

1

Endorecherche, Inc.: WO08124922

steroidal (pure) antagonists of Shionogi cells in vitro and VP/SV in vivo

NC

OH

R 1

N

O

R 1 = Me (82) 0.9 nM = IC 50 in SC115 cells R 1 = F (83) 2.5 nM = IC 50 in SC115 cells

cmpd R 1

R 2

R 3 AR IC 50 (nM)

SV wt (% of intact control)

cmpd R 1

R 2 saturation AR IC 50 (nM)

78 M e H double bond 1420

79 H H single bond 19880 H F single bond 14481 H OH single bond

141

cmpd R

1/R 2 R 3/R 3′

R 4

R 5

84 m -CF 3, o -F cyclobutyl F –C(O)NH M e 85 m -CF 3, o -F di-M e F –C(O)NH M e

86 m -Cl, o -F di-M e H CN

87

m -OMe, o -F di-M e H CN

Figure 9.In vivo screened competitive androgen receptor (AR)antagonists.

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E x p e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a r y o n 01/14/13

F o r p e r s o n a l u s e o n l y .

without any significant agonism activity.86bears a 4,4￠-dimethyl substitution on the thioimidazolidinone ring,electron withdrawing groups on the A-ring (CN,Cl and F),and p-CN on B-ring,and 86displayed the best IC 50(92nM)in LNCaP cells.General SAR shows that the spiro analogs are less active (IC 50range 380--2400nM)than the dimethyl-substituted thioimidazolidinones (IC 50range 92--1800nM).In LNCaP viability assays,84(spiro analog)and 86inhibited viability by 91%and 85and 87by 87%whereas 62at the same concentration (2.5μM)demonstrated 21%inhibition.85dosed topically as 0.2and 1%solutions (in PEG/EtOH)demonstrated 2.8and 3.7scores (0is no hair growth and 4is hair growth in shaved area similar to surrounding area)for promoting hair growth in vivo in a C57BL/6mouse model in comparison with known RU-58841(phenylhydantoin with left-side phenyl ring replaced by n-pentanol side chain)only producing a score of 1.9.

2.5

Noncompetitive antagonists

Agents that do not compete with androgens for binding of the LBD are termed as noncompetitive antagonists in this review.Ligand-dependent (activation by endogenous androgens that bind to the LBD)and ligand-independent (activation by cAMP,IL-6,forskolin)AR transactivation both require the NTD for their activity.The activating function-1(AF-1),located in the NTD,contributes a large amount to the tran-scriptional activation function of the AR as compared with the activating function-2(AF-2;located in the C-terminal domain).Further,the NTD contains ~95%of the phospho-rylation sites of the AR,which are required for transactivation.Cumulatively,these suggest that the NTD would be a good target in AR-dependent disease states such as prostate cancer,even if these disease states are not sensitive to androgen with-drawal.This is corroborated by evidence using AR-NTD decoys (AR1-558),which are inhibitors of prostate cancer tumors that require the AR [109].

Although the initial design of noncompetitive antagonists is difficult because of the lack of any structural information about the AR-NTD and evidence that it is highly flexible and intrinsi-cally disordered in solution,several other factors suggest it would be a superior target to the LBD antagonists,which are currently used in conjunction with androgen deprivation therapy.For instance,very few of the disease-associated muta-tions of the AR fall into the NTD,suggesting fewer problems with resistance to noncompetitive antagonists.Also the NTD is the least conserved (only ~15%)domain across the steroidal receptor family,suggesting that cross-reactivity with other ste-roid receptors would be unlikely.Unlike other steroid receptors,the primary interface between co-factors and the AR is in the NTD domain,indicating that a noncompetitive antagonist would be able to block ligand-dependent or ligand-independent AR transactivation,and hence should be equally potent in hormone-sensitive and castration-resistant prostate cancers.Moreover,a noncompetitive antagonist would theoreti-cally remain effective against a number of resistance

mechanisms that ultimately limit the clinical utility of tradi-tional anti-androgens.These include increased androgen concentrations,AR-signaling occurring in the absence of ligand,activating AR LBD mutants and active AR splice variants lacking an LBD.Molecules have been reported to interfere with both co-factor recruitment and receptor DNA interactions with mixed success [110].Molecular features of the AR allow it to accommodate bulkier co-regulator interaction domains providing potential for selective antagonism of AR signaling over other closely related receptors [111,112].The specificity of DBD-targeted approaches is expected to pose a greater challenge given the relative similarities of DNA-binding elements among the nuclear hormone receptors [113,114].The principal challenge in either case is probably determining a high-affinity selec-tive interaction to mitigate potential off-target effects.The relatively recent characterization of these protein --protein or protein --DNA interactions,and dearth of structural data,add to the difficulty of such drug discovery efforts.Very few reports of noncompetitive antagonists exist as of yet,as reviewed below.

2.5.1

British Columbia Cancer Agency and The University of British Columbia --bisphenol A (88)diglycidic ethers (BADGE)as noncompetitive antagonists

Sadar et al.in a series of applications reported several novel bisphenol A (88)(Figure 10)diglycidic ether (BADGE)derivatives as AR antagonists in vitro .These compounds were designed based on the fortuitous discovery of BADGE derivatives in marine sponges and their testing for AR activity as reported in WO10000066[115].The compounds isolated from the sponge extracts were diether derivatives of 88,which could be easily made from commercially available materials.The lead compound 89[116](Figure 10)inhibited transcription of a C-terminally truncated AR (IC 50of 6.6μM),which consisted of amino acids 1-558,thus lacking the LBD (AF-2)but possessing the AF-1of the NTD.In full-length AR,89demonstrated antagonism of R1881-mediated PSA mRNA induction,but had no effect in in vitro transcriptional assays for GR and PR activity.89prevented nuclear localiza-tion and inhibited N-to C-terminal interaction.Thus 89was characterized as inhibiting AR-induced transcription by preventing N/C interaction (i.e.,through AF-1interference).LNCaP anti-proliferation equipotent to bicalutamide was reported as measured by BrdU incorporation but no effect was seen in the androgen-independent PC3proliferation,suggesting AR dependence.LNCaP xenografts possess AR but develop androgen independence following castration.In a castrated LNCaP xenograft model,intratumoral 89at 20mg/kg every 5days (initiated 1week after castration)reduced xenografts from ~100to 35.4mm 3,whereas DMSO-treated xenografts increased to 436mm 3.Intravenous (tail vein)89also reduced tumor volumes albeit with less efficacy (106mm 3was reduced to 64mm 3)when dosed at

M.L.Mohler et al .

556

Expert Opin.Ther.Patents (2012)22(5)

E x p e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a r y o n 01/14/13

F o r p e r s o n a l u s e o n l y

.

a higher level (50mg/kg every 5days),suggesting bioavailabi-lity may be limiting efficacy.AR protein levels in the treated xenograft tumors were not reduced as demonstrated using immunohistochemistry and western blot analyses.PC3xeno-grafts were also studied because of their dependence on the

NTD AF-1activity for AR transcriptional activation.Consis-tent with in vitro data,the efficacy in PC3xenografts was reduced,with 20mg/kg only slightly slowing the xenograft growth (i.e.,no regression as in LNCaP xenografts).

HO

OH

bisphenol A (88)

9091

O

O

NC

OH

Cl

O

O

Cl

OH

89

Sponge extract

O

O

Cl

OH

HO

OH

WO11082487

WO11082488

93

O

O

NC

OH

Cl

O

O

O

O

NC

Cl

92

NH

O

O

O

NO 2

O

O

94University of Texas, Austin: W011150360

oligo-benzamides as non-competitive antagonists that block AR translocation, AR genomic activity and prostate cancer cell proliferation

British Columbia Cancer Agency & University of British Columbia: WO10000066, WO11082487 and WO11082488 bisphenol A (88) diglycidic ethers (BADGE) as non-competitive antagonists

NH

O

Y

X

O

R 1

O

R 2

R 1, R 2 = various alkyl

X, Y = H, various peptide chains,

various esters

NH

O X

O

R 1

O

R 2

NH

O NH

O O O

NO 2

O

O

NH

O O O

NO 2

O

O

98

IC 50 = 20 nM 99

IC 50 = 26 nM

WO10000066

Figure 10.Patented noncompetitive androgen receptor (AR)antagonists.

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Expert Opin.Ther.Patents (2012)22(5)

557

E x p

e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d

f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a r y o n 01/14/13F o r p e r s o n a l u s e o n l y .

T a b l e 3.O v e r v i e w o f s e l e c t e d a n d r o g e n r e c e p t o r (A R )a n t a g o n i s t s p a t e n t e d i n 2008--2011.

C m p d n o .(g r o u p )

B i n d i n g o r t r a n s a c t i v a t i o n

A R t a r g e t g e n e o r p r o l i f e r a t i o n

N u c l e a r t r a n s l o c a t i o n i n h i b i t i o n S A R D a c t i v i t y P a n -a n t a g o n i s m H e r s h b e r g e r o r x e n o g r a f t d a t a O t h e r d a t a o r c o m m e n t s

1(M e d i v a t i o n )[79]

21.4n M b i n d i n g v s 11.5n M f o r 18F -16b F D H T

A n t a g o n i s m a n d n o a g o n i s m o f P S A a n d T M P R S S 2g e n e s N u c l e a r t o c y t o p l a s m i c r a t i o (10μM ):3.0v s 29a n d 14f o r R 1881a n d b i c a l

N o p r o t e i n d e g r a d a t i o n a t 10μM i n L N C a P -A R c e l l s S u p p r e s s e d L N C a P g r o w t h ;A n t a g o n i z e d W 741C t r a n s a c t i v a t i o n

10m g /k g p r o d u c e d ~10--65%r e d u c t i o n i n L N C a P -A R x e n o g r a f t

T r a n s l o c a t i o n i n h i b i t o r :P h a s e I I I c l i n i c a l c a n d i d a t e ;i n c r e a s e d s e i z u r e r i s k p r o b a b l y d u e t o G A B A A r e c e p t o r a n t a g o n i s m i n t h e C N S

2(A r a g o n )[78]

16.0n M b i n d i n g v s 11.5n M f o r 18F -16b F D H T

A n t a g o n i s m a n d n o a g o n i s m o f P S A a n d T M P R S S 2g e n e s

N u c l e a r t o c y t o p l a s m i c r a t i o (10μM ):2.5v s 29a n d 14f o r R 1881a n d b i c a l N R

N R

>50%r e d u c t i o n a t 10m g /k g i n 8/10L N C a P -A R x e n o g r a f t s

T r a n s l o c a t i o n i n h i b i t o r :P h a s e I /I I c l i n i c a l c a n d i d a t e ;a l s o b i n d s G A B A A r e c e p t o r b u t l o w e r b r a i n l e v e l s t h a n 1;h i g h e r t u m o r /p l a s m a r a t i o t h a n 1

19(U n i v .M D ,B a l t i m o r e )405n M (w t A R b i n d i n g )

I C 50o f 2.6--6.0μM i n L N C a P a n d L A P C 4c e l l s i n v i t r o

N R ~90%d e c r .i n A R l e v e l s i n L N C a P (1--15μM )a n d L A P C 4(15μM )B i n d i n g o f 845a n d 454n M t o T 877A a n d T 575A ,r e s p e c t i v e l y 0.13m m o l /k g s u b c u t .t w i c e d a i l y p r e v e n t e d L A P C 4t u m o r f o r m a t i o n

S A R D :L y a s e i n h i b i t i o n o f 300n M ;P o o r o r a l b i o a v a i l a b i l i t y

32(A s t r a Z e n e c a )N R

N R N R p I C 50=6.45o r ~300n M ;s e e a l s o C o m m e n t s

N R

N R S A R D :R e d u c e d A R p r o t e i n l e v e l s d e t e c t e d b y E L I S A i n L N C a P c e l l s

45(U n i v .o f D e l a w a r e )

I C 50=3.5μM (w t A R t r a n s c r i p t i o n )

N R 100μM p r e v e n t e d n u c l e a r l o c a l i z a t i o n o f A R -G F P

~60%d e c r .i n A R l e v e l s i n L N C a P (50μM )a n d C W 22R v 1(100μM )c e l l s

T r a n s c r i p t i o n (I C 50

(μM )):T 877A (4.5),W 741C (5.9),a n d W 741L (12.2)

N R P a n -a n t a g o n i s t :57(T a k e d a )

b i n d i n g (%i n h a t 1μM ):49(w t A R )a n d 79(T 877A )

P S A (%i n h a t 1μM ):110.2

N R N R

T r a n s c r i p t i o n (%i n h a t 1μM )i n W 741C :38

N R P a n -a n t a g o n i s t :

82(E n d o -r e c h e r c h e )N R

0.9n M a n t a g o n i s m o f D H T -i n d u c e d S C 115c e l l p r o l i f e r a t i o n

N R

0.1m g o r a l l y r e v e r s e d D H T -m e d i a t e d v e n t r a l p r o s t a t e a n d s e m i n a l v e s i c l e s g r o w t h i n v i v o

I n v i v o s c r e e n i n g :

74(B r i s t o l -M y e r s S q u i b b )

I C 50=31n M (w t A R t r a n s c r i p t i o n )

N R N R N R N R

3m g /k g o r a l l y f o r 4d a y s :37%o f i n t a c t c o n t r o l s e m i n a l v e s i c l e s w e i g h t

I n v i v o s c r e e n i n g :

N R :N o t r e p o r t e d .

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E x p e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a r y o n 01/14/13

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.

A number of other sponge isolates of similar BADGE structure were also reported in WO10000066.

Synthetic derivatives such as 90--91(Figure 10)of the sponge isolates retaining the dimethyl linker of 88were reported in WO11082487[117].Other synthetic derivatives with a methanone linker such as 92--93(Figure 10)were reported in WO11082488[118].Both sets of compounds were qualitatively characterized as low-μM range antago-nists of R1881-mediated PSA reporter gene expression in LNCaP cells.

2.5.2

University of Texas,Austin --oligo-benzamides as noncompetitive antagonists that block AR

translocation,AR genomic activation and prostate cancer cell proliferation

Ahn &Ganesh in W011150360[119]investigated oligo-benzamide peptidomimetics that interfere with the interaction between AR and PELP-1(and Hsp27),a scaffolding protein known as a nuclear receptor (NR)Box protein.These rationally designed noncompetitive ligands mimic the LXXLL sequence (i.e.,the NR Box)in PELP-1that interacts with AR.This inter-action is required for both genomic and non-genomic signaling,so it represents a novel area of focus for AR antago-nism.The oligo-benzamides modulate protein --protein,protein --peptide and protein --drug interactions to exert a variety of physiological consequences.

The bis-(and tris-)benzamide peptidomimetic scaffold mimics the presentation of amino acids along a single face of an a -helix by rigidly orienting two (or three for the tris-benzamide scaffold)functional groups isosterically relative to the side chains of the i and i +4(and i +7for tris -benzamides)amino acids of the helix.Their initial di-isobutyl di-benzamide 94(Figure 10)was based on the LXXXL motif and was an attempt to target all 10LXXLL motifs that bind the AR.Like-wise the di-benzyl di-benzamide 95(not shown)was synthesized as a control.94(100nM)but not 95was able to block DHT-induced AR --PELP-1protein --protein interaction in LNCaP cells as evidenced by co-immunoprecipitation experiments.This dose-dependent ability was also seen for DHT-and estradiol-induced AR --PELP-1protein --protein interaction in LAPC4,C4-2,VCAP and CW22-Rv1cells.94was also able to suppress expression of DHT-induced genes,AR transactivation and prostate cell line proliferation in a variety of cancer cell lines,and these effects were rescued by overexpres-sion of PELP-1.Further,94showed antitumor activity in xeno-grafts;however,the dose/route and cell line were not readily discernible from the figures.94did not reduce DHT-mediated non-genomic [120]AR activity,but did block DHT-induced nuclear translocation.

A series of derivatives of 94depicted by the general structure 96(Figure 10)was synthesized that mostly explored N-terminal and C-terminal capping groups (esters,amides,peptides,etc.),and some conservative variation of the side chains.Also a series of tri-benzamide derivatives depicted by general structure 97(Figure 10)was synthesized.These

T a b l e 3.O v e r v i e w o f s e l e c t e d a n d r o g e n r e c e p t o r (A R )a n t a g o n i s t s p a t e n t e d i n 2008--2011(c o n t i n u e d ).

C m p d n o .(g r o u p )

B i n d i n g o r t r a n s a c t i v a t i o n

A R t a r g e t g e n e o r p r o l i f e r a t i o n

N u c l e a r t r a n s l o c a t i o n i n h i b i t i o n

S A R D a c t i v i t y

P a n -a n t a g o n i s m

H e r s h b e r g e r o r x e n o g r a f t d a t a

O t h e r d a t a o r c o m m e n t s

89(B r i t .C o l u m b i a U n i v .)[116]

I C 50=6μM (t r a n s c r i p t i o n o f A R N T D (A R 1-558))B l o c k s A F 1-a n d A F 2-d e p e n d e n t P S A g e n e i n d u c t i o n s a n d L N C a P c e l l p r o l i f e r a t i o n D o e s n o t i n d u c e t r a n s l o c a t i o n a n d p a r t i a l l y b l o c k s R 1881a c t i v i t y a t 10μM N R

D e s c r i b e d t h a t t h e o r e t i c a l l y s h o u l d w o r k f o r A R e s c a p e m u t a n t s D o s e d a t 50m g /k g i.v .q o d :r e d u c e d V P b y ~20a n d ~50%r e d u c t i o n i n L N C a P t u m o r s i z e

N o n c o m p e t i t i v e (o r N T D -d i r e c t e d )a n t a g o n i s t :94(U n i v .o f T e x a s ,A u s t i n )

N R

S u p p r e s s e d D H T -i n d u c e d g e n e e x p r e s s i o n s a n d c e l l p r o l i f e r a t i o n s

B l o c k e d D H T -i n d u c e d n u c l e a r t r a n s l o c a t i o n

N R N R

R e p o r t e d l y a c t i v e (u n k n o w n d o s e /r o u t e )

N o n c o m p e t i t i v e (o r N T D -d i r e c t e d )a n t a g o n i s t :B l o c k e d A R -P E L P 1p r o t e i n :p r o t e i n i n t e r a c t i o n s i n L A P C 4,C 4-2,V C A P a n d C W 22-R v 1c e l l s

N R :N o t r e p o r t e d .

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.

derivatives were screened in anti-proliferative prostate cancer cell lines,producing IC 50values as low as 20.2(98)and 26.2nM (99),which is an improvement compared with 94.Some of the more potent derivatives were also shown to inhibit the AR --PELP-1interaction.

3.

Conclusions

The field of anti-androgens is exciting from the perspective that it has recently produced a strong clinical candidate and a plethora of new mechanistic insights,revitalizing a field that has not seen a market approval since bicalutamide in 1995[30].Clearly,the strongest second-generation anti-androgen is 1(translocation inhibitor)whose superior activities in novel models of CRPC resulted in its clinical evaluation in patients with progressive CRPC and is currently a Phase III clinical candidate.

3.1

Patented LBD-directed antagonists

The diversity of characterizations in the preclinical pipeline reflects the advancement in the understanding of the mecha-nisms by which AR axis functions.Correspondingly,the complexity and heterogeneity of anti-androgen biological profiles have increased.This is particularly true for the LBD-directed antagonists where several groups have found novel mechanisms of anti-androgenicity as compared with bicalutamide and other first-generation anti-androgens.Exam-ples of novel mechanisms discussed in this review include,among others,inhibition of nuclear translocation,selective downregulation/degradation of the AR (collectively discussed as SARDs herein)and pan-antagonism.Confusing the issue further is that these mechanisms are in no way mutually exclu-sive as exemplified by 1(nuclear translocation inhibitor and pan-antagonist),19(SARD,lyase inhibitor,pan-antagonist),45(pan-antagonist,SARD,translocation inhibitor),as reviewed supra and summarized in Table 3.

Unfortunately,the SARDs and pan-antagonists to date have not demonstrated high potency or the high potency is obscured by the reporting format in the patent literature,which was often qualitative or efficacy data at a single (high)concentra-tion.The most potent patented SARD reviewed herein was 32with a pIC 50value of 6.45(or ~300nM)and the most potent pan-antagonist was 57with an average IC 50value across mutants tested of <1μM (all data reported as efficacy at 1μM)(Table 3).Further traditional in vivo approaches have produced a couple of highly potent and orally active pure antagonists.In castrated rats,82only required 0.1mg per rat to reverse DHT-induced seminal vesicle and ventral prostate growth (Table 3).Similarly,4mg/kg orally of 74inhibited sem-inal vesicle growth to 37%of intact control (Table 3).

3.2

Patented noncompetitive antagonists

89,described as a small-molecule inhibitor of the AR-NTD,typifies the novel noncompetitive antagonist [116].Of note,89

displays many ideal features of a CRPC therapy including

inhibition of many NTD-mediated downstream effects of both androgen-dependent and androgen-independent AR acti-vation,effective antagonism of LBD-less AR splice variants,apparently specific inhibition of AR (only GR and PR excluded)and efficacy in mouse CRPC models without any detected toxicity (Table 3).However,the requirement of intra-venous dosing and the limited length of treatment (seven doses over 15days)suggest considerable room for optimization.Although the characterization of 94stops short of providing an in vivo proof of concept,the rational design of 94based on PELP-1is very interesting and shows promise for further development (Table 3).Two patented [121]compounds,harmol hydrochloride and pyrvinium pamoate,were later reported as noncompetitive antagonists.These and other noncompetitive antagonists from the peer-reviewed literature have recently been reviewed [122].

4.

Expert opinion

The most promising compound is 1as the extensive clinical data suggest improved efficacy relative to https://www.doczj.com/doc/fa9105297.html,-pleted Phase II trials with 1demonstrated quite promising results in heavily treated progressive CRPC patients [80].Further their Phase III AFFIRM trial in men with advanced prostate cancer previously treated with docetaxel-based chemotherapy recently reported favorable interim analysis data that showed that 1significantly improved survival compared with placebo (press release from Medivation on 3November 2011).Medivation is also looking at chemo-therapy and hormone-naive patients in separate Phase III and Phase II trials,potentially providing broad coverage of the various stages of prostate cancer.Although this has been characterized as a translocation inhibitor,it is also clear that this compound is strikingly more potent than bicalutamide in several contexts studied.It is possible that the relative potency and favorable pharmacokinetic profile confer the improved in vivo and clinical efficacies to 1,rather than translocation inhibition or other novel mechanistic explanations.

There is a pipeline of preclinical compounds with improved biological profiles compared with the first-genera-tion anti-androgens.Although interesting,the variety of novel mechanistic characterizations may add little prognostic value with regard to clinical prospects.For instance,thus far SARD activity has required high concentrations relative to other mechanisms of anti-androgenic action,which differs from the somewhat more familiar case of selective estrogen receptor degraders (SERDs).The clinically approved SERD fulvestrant has both very potent antagonism and quantitative receptor turnover properties [120].Mechanistic studies suggest that upon binding ER a ,fulvestrant elicits a conformation change that results in sequestration to an insoluble cellular fraction and subsequent proteosomal degradation [120,123].Careful control experiments,almost universally omitted from descriptions in the patent literature of other receptor degraders,have shown this process to be distinct from the

M.L.Mohler et al .

560

Expert Opin.Ther.Patents (2012)22(5)

E x p e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a r y o n 01/14/13

F o r p e r s o n a l u s e o n l y

.

螺栓强度等级对照表

钢结构连接用螺栓性能等级分3.6、4.6、4.8、5.6、6.8、8.8、9.8、10.9、12.9等10余个等级，其中8.8级及以上螺栓材质为低碳合金钢或中碳钢并经热处理（淬火、回火），通称为高强度螺栓，其余通称为普通螺栓。螺栓性能等级标号有两部分数字组成，分别表示螺栓材料的公称抗拉强度值和屈强比值。例如，性能等级4.6级的螺栓，其含义是： 1、螺栓材质公称抗拉强度达400MPa级； 2、螺栓材质的屈强比值为0.6； 3、螺栓材质的公称屈服强度达400×0.6=240MPa级性能等级10.9级高强度螺栓，其材料经过热处理后，能达到： 1、螺栓材质公称抗拉强度达1000MPa级； 2、螺栓材质的屈强比值为0.9； 3、螺栓材质的公称屈服强度达1000×0.9=900MPa级 螺栓性能等级的含义是国际通用的标准，相同性能等级的螺栓，不管其材料和产地的区别，其性能是相同的，设计上只选用性能等级即可。强度等级所谓8.8级和10.9级是指螺栓的抗剪切应力等级为8.8GPa和10.9Gpa 8.8公称抗拉强度800N/MM2 公称屈服强度640N/MM2 一般的螺栓是用"X.Y"表示强度的， X*100=此螺栓的抗拉强度， X*100*（Y/10）=此螺栓的屈服强度 （因为按标识规定：屈服强度/抗拉强度=Y/10）

=============== 如4.8级 则此螺栓的 抗拉强度为：400MPa 屈服强度为：400*8/10=320MPa ================= 另：不锈钢螺栓通常标为A4-70，A2-70的样子，意义另有解释度量 当今世界上长度计量单位主要有两种，一种为公制，计量单位为米（m）、厘米（cm）、毫米（mm）等，在欧州、我国及日本等东南亚地区使用较多，另一种为英制，计量单位主要为英寸（inch），相当于我国旧制的市寸，在美国、英国等欧美国家使用较多。 1、公制计量：（10进制） 1m =100 cm=1000 mm 2、英制计量：（8进制） 1英寸=8英分 1英寸=25.4 mm 3/8￠￠×25.4 =9.52 3、1/4￠￠以下的产品用番号来表示其称呼径，如： 4#， 5#， 6#， 7#， 8#， 10#， 12# 螺纹 一、螺纹是一种在固体外表面或内表面的截面上，有均匀螺旋线凸起的形状。根据其结构特点和用途可分为三大类：

酒店各部门岗位职责与操作流程

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f.硬家具：干净明亮，无划伤痕迹，位置正确； g.软家具：无尘无迹无杂物； h.抽屉：干净，使用灵活自如，把手完好无损； e.电话机：功能正常，无尘无迹，指示牌清晰完好，话筒无异味； f.镜子与书柜：框架无尘，镜面明亮，位置端正； g.灯具：灯泡清洁，功能正常，烟罩清洁，使用正常； h.垃圾桶：清洁、状态完好； i.电视：使用正常，频道应设在中央一台，音量调到偏低，画面与音响效果较好； j.壁柜：衣架的数量、品种正确且干净无污，门、柜底、柜壁和格架清洁完好； k.窗户：清洁明亮，窗台与窗柜干净，开启灵活； l.窗帘：干净、完好，使用自如； m.空调：滤网清洁，运作正常，温控符合要求； n.酒吧：清洁无异味，物品齐全； o.客用品：数量、品种正确，状态完好，摆放符合规格； B：卫生间： a.门：前后两面干净，状态完好； b.墙面：清洁，无污迹； c.天花板：无尘无迹，完好无损； d.地面：清洁无尘，无毛发，接缝处完好； e.浴缸：内外清洁，镀铬件干净明亮，皂缸干净，浴缸塞、沐浴器、排水阀和水管开关等清洁完好，接缝干净无斑迹，浴帘干净完好，浴帘扣齐全，晾衣绳使用自如； f.脸盆及梳妆台：干净，镀铬件明亮，水阀使用正常，镜面明净，灯具完好； g.座厕：里外都清洁，使用状态良好，无损坏，冲水流畅； h.抽风机：清洁，运转正常，噪音低，室内无异味；

PA主管工作职责及流程

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酒店管家工作职责范本

岗位说明书系列 酒店管家工作职责（标准、完整、实用、可修改）

编号：FS-QG-69513 酒店管家工作职责 Hotel housekeeper job responsibilities 说明：为规划化、统一化进行岗位管理，使岗位管理人员有章可循，提高工作效率与明确责任制，特此编写。 酒店管家职责 一、酒店管家的职责WHATDOESAHOTELBUTLERDO 是负责处理客人的需求、预约、预定、问题、投诉;监督和协调客人所接受的各项服务;关注客人入住整流器个过程中的各项服务，确保客人满意而归。 二、酒店为何要设立管家部门WHYHAVEABUTLERDEPARTMENT 现代酒店的部门分工非常明确，但客人在酒店的逗留期间，所需要的服务通常是需要两面三刀个部门或多个部门协同工作来完成的;且各部门也本可以通过部门间的信息传递和帮助来提高自身的服务水平;然而这种协同服务的模式在丙代酒店中仍不常见。管家接受了多主面服务的培训，能够协同酒店任何一个部门的工作。他们并非隶属于某一部门，

其职现就是让客人满意。只有管家服务才是真正的无缝服务，因为管家能够从客人处或其他部门处获得信息，传递信息或执行任务，使客人满意。通过建立有效的汇报程序，管家成了酒店高级管理层的耳目，确保管理部门的监督工作，保证客户在酒店逗留期间一切总是均能得到期妥善解决，生舒心，满意而归。 三、什么是酒店管家式服务酒店管家式服务:是 酒店内的管家为客人所提供的服务，其中又有“大管家”和“酒店管家”二种概念; *“大管家”发挥着酒店全面服务的协调作用。 *“酒店管家”则是在客人一旦入住酒店，以客人“私人管家”的身份，成为套房(家庭)的“经理”、客人的雇员;行使充当客人“私人助理”职责，处理客人的要求、预约、预定、问题、投诉;监督和协调客人所接受的各项服务;通过关注客人入住整个过程中的各项细节，确保客人满意而归。 四、21世纪的管家培训:BUTLERTRAININGFORTHE21STCENTURY: *英国专业管家行会设置的培训课程旨在培养赏在照顾

PA主管岗位职责

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六、制定本区域的工作标准和服务程序。 For the regional standard of work and service programs. 七、负责本部门员工的培训和考核工作。 Responsible for departmental staff training and assessment work. 八、负责每天工作情况的记录和汇报。Be responsible for daily work record and report 九、认真检查本组人员的仪容仪表。Carefully check staff grooming 十、做好与其它部门的协调工作。Do well with other departments' coordination work. 十一、监督本部门日常工作，确保本部门各环节、各项工作与服务质量达标。Supervise the daily work, ensure the department each link, various departments work and service quality. 十二、完成上级交办的其它工作。Finish other jobs assigned by

PA岗位职责

JOBDESCRITION 岗位职责 公司名称：万行国际酒店管理公司 Company:WanXingInternationalManagemen tGroup 编号：PA001 ReferenceNo: 部门：房务部 Department:GuestRoomDepartment 日期： Date 2011-2 职位：PA主管Position:PASupervisor 页：1/1 Page 职级/ClassofPosition：四级 直属上司/DirectSuperior：房务部经理 直属部下/DirectSubordinates：PA领班 岗位职责/Responsibilities 1、遵守酒店和部门制定的规章制度，包括工作时间、纪律和酒店设施的使用。 2、对房务经理负责。 3、主持班前班后会，传达部门会议精神。 4、检查属下员工的签到情况。 5、负责检查下属员工的仪容仪表，保持良好的形象。 6、安排、分派PA部日常清洁管理工作并不断巡视公共区域，确保清洁工作的完善。 7、处理任何在公共区域发生的事情，并将处理结果及时汇报给房务经理。 8、负责训导及讲解一切清洁事项及配合机器的运作。 9、熟悉管辖范围内的各岗位职责和清洁用品的配比使用及各项清洁工作的操作规程。 10、督导下属员工的工作并监察其工作表现及操作，保证PA员工的仪容、礼貌合符酒店要 求。

11、指导属下员工做好公共区域内之花卉植物的生长、摆放、清洁等达到美化效果。 12、负责安排员工对客房地毯和地板定期或不定期的清洁保养工作。 13、检查在公共区域内任何会导致酒店受损或发生火警之可能性。 14、处理PA员工在工作中出现的问题，协助他们解决困难，协调上下级关系，以保证工作有效实施。 15、做好PA服务用具及设备的清洁保养工作，及时报告损坏和丢失情况，认真填写报告。 16、检查和控制PA所需物品及清洁用品的耗用，对清洁费用成本控制，杜绝浪费及屯积。 17、负责PA部每月的盘点工作。 18、负责对属下员工的工作表现评估，留意属下员工的思想动向，做好思想工作。 19、完成上级交办的其他工作。 20、 制表人/PreparedBy：盘忠强审批人/ApprovedBy： 职位/Position：房务经理职位/Position：总经理 签名/Signature： 日期/Date：2011 年2月 签名 /Signature： 日期/Date： JOBDESCRITION 岗位职责 公司名称：万行国际酒店管理公司 Company:WanXingInternationalManagemen tGroup 编号：PA002 ReferenceNo: 部门：房务部 Department:GuestRoomDepartment 日期： Date 2011-2 职位：PA领班Position:PACaption 页：1/1 Page

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PA部管理制度及操作规范

富业大酒店PA部管理制度及操作规范 一、PA的含义 酒店PA是酒店Public Area的简称,一般特指公共区域保洁员;PA区域,一般指公共区域. 二酒店PA一般包括主管、领班和员工. 三酒店PA部门的岗位职责 (一)、主管岗位职责 通过对下属的督导，培训及安排和对清洁用品的合理使用来达到服务水准，通过对植物的培育和布置的管理，给宾客一个赏心悦目的环境，具体职责有： 1、检查各公区领班是否督导下属员工工作，达到应有的清洁保养效果。 2、巡查各区域花草树木及绿化设施，负责制定绿化期养护工作计划，掌握计划的执行的情况，确保工作质量和进度，保证绿化系统的良好动作。 3、督导各区域领班的管理工作，制定各项清洁设备的管理使用和保养计划，定时检查客用品的使用控制情况。 4、制定和编排公共区域大清洁工作计划、防疫（杀虫）、工作计划和人力安排计划。 5、负责员工的业务培训和纪律教育，确保员工的言谈举止、服务质量符合饭店的标准。

6、负责员工的排班、考勤和休假审核，根据客情需要及员工特点安排日常工作，调查日常工作发生的问题，做好重大节日、重要会议、 宴会和贵宾到访之前的布置检查工作，做好与各有关部门的沟通和协调工作。 7、完成上级布置的其他工作。 (二)、领班岗位职责 通过对服务员的督导、培训和物品的安排使用，达到饭店服务水准，具体职责有： 1、每日班前看交接薄及留意当日公共区域主管提示。 2、检查员工签到记录，合理安排下属员工工作。 3、检查所辖范围的清洁保养效果。 4、随时检查员工的工作情况，检查清洁用品及器具等，并及时进行调整，发现异常情况及时汇报。 5、指导及评估下属的工作质量。 6、负责员工的业务培训，提高他们的清洁保养技术。 7、完成上级布置的其他任务。 (三)、员工岗位职责 通过对公共区域清洁、保养工作，为宾客提供舒适、干净、方便的生活环境，具体职责有： 1、根据领班的工作安排，清洁保养所属的公共区域。 2、检查责任区域各种设备设施和家具的完好情况，及时报告和报修。 3、做好清洁机械的保养和清洁用品的保管的使用，整理好库房。

酒店管家部职责范围

岗位说明书系列 酒店管家部职责范围（标准、完整、实用、可修改）

编号：FS-QG-48616酒店管家部职责范围 Hotel butler's responsibilities 说明：为规划化、统一化进行岗位管理，使岗位管理人员有章可循，提高工作效率与明确责任制，特此编写。 酒店管家部的职责范围: 管家部是负责酒店公共场所、客房的清洁卫生及绿化布置的工作。为宾客提供舒适、干净、方便、美的生活享受。管家部工作的好坏，直接影响到客人对酒店的印象，关系到酒店的声誉。因此，每个员工都要树立“宾客至上、服务第一”的宗旨，不断提高酒店意识，服务意识，从细微处着手;不断提高服务质量，让客人高兴而来XX，满意而离开XX。具体职责范围: 1、负责酒店内外的环境卫生工作，重点抓好酒店大堂清洁，一、二层公共场所卫生间清洁。做到地面无杂物，家具无灰尘，卫生无死角; 2、负责酒店楼层和客房的清洁工作，客用物品的更换补充;

3、负责酒店的绿化布置工作，不断完善酒店的美化环境。及时做好花草树木的修剪、栽培及鱼、鸟的管养工作。保持大小鱼池及水池的清洁; 4、负责酒店大堂接待处、客房、会议室、餐厅等各部门的盆景及插花，负责各会议、宴会的绿化设计和布置，不断提高艺术服务水平; 5、负责花场的管理工作，做好苗木的保养和培殖工作; 6、切实做好卫生防疫工作，定期在酒店内外喷洒药物，杜绝四害。确保酒店内外环境安全卫生; 7、加强绿化工具、清洁工具的维护保养工作，培训专业技术人才; 8、树立整体经营思想，开源节流，控制好成本，减少费用开支。 请输入您公司的名字 Foonshion Design Co., Ltd

PA岗位职责

pa部岗位职责 1．准时打卡上下班，准时参加例会， 认真听取部长的工作安排及表彰和处罚。 2．负责公司的日常清洁服务工作。 3．做好营业前的一切区域卫生工作， 负责领取工作中的所需物品。 4．上班时随时关注区域卫生情况，不 准串岗与其他部门和本部门的工作人员闲聊，以及不能私自离岗，串岗。 5．按照服务规范和程序做好清洁卫 生工作。 6．在营业中发现问题及时处理，如有 处理不好的应及时向部门领导汇报，不能私自做主。 7．及时补充各种物品，做好回收工 作。 8．认真完成上级交给的任务，随时注 意个人卫生。 9．见到领导要打招呼。 10．及时向上级报告所负责区域设 备的保养和损坏情况。 11．如遇突发事件，保持头脑清醒， 及时做好相应的处理措施。 12．在公司内所检拾的物品，及时上 缴给上级。 13．做好各项硬件的卫生清洁工作， 保证洗手间、垃圾桶无异味。 14．在工作中要不断巡岗，做到看到 哪里脏搞好那里的卫生，按规定标准。 15．立式垃圾桶里面的垃圾桶要不 定期清洗，做好一些设施设备的保养工作。篇二：pa员工岗位职责 pa员工岗位职责 （1）对领班负责，按规定的程序做好公共区域的清洁工作。 （2）负责公共区域所有陈设装饰去渍、上蜡、除尘清洁保养工作。 （3）负责公共区域的各种地面、墙面、天花板的清洁保养。 （4）负责公共区域客用洗手间的清洁、整理和服务工作。 （5）负责公共区域客梯、外围及大堂的清洁保养工作。 （6）负责公共区域所有灯具、铜器、不锈钢制品等清洁保养工作。 （7）负责公共区域内部个幕墙玻璃及镜面的清洁维护工作。 （8）巡视公共区域，随时进行清洁保养工作。 （9）管理好公共区域的机器、客用品清洁用品等各种用品。 （10）完成上级布置的其他各项服务。 （11）负责酒店内所有地毯和沙发的清洁。 pa规章制度 1、做为一名pa员工，首先要严格遵守酒店的各项规章制度。 2、对本职工作要主动热情、爱岗敬业、责任心强、认真仔细、好学上进。

五星级酒店管家部岗位职责

五星级酒店管家部岗位 职责 Document number【AA80KGB-AA98YT-AAT8CB-2A6UT-A18GG】

职位工作描述JOB DESCRIPTION （JD） 管家部 Housekeeping Department 目录Contents HK-JD-01 管家部简介 管家部 HK-JD-01行政管家职位工作描述 HK-JD-02房务中心职位工作描述 HK-JD-03楼层主管职位工作描述 HK-JD-04楼层领班职位工作描述 HK-JD-05楼层服务员职位工作描述 HK-JD-06仓库保管员职位工作描述 HK-JD-07消毒工职位工作描述 HK-JD-08PA主管职位工作描述 HK-JD-09PA领班职位工作描述 HK-JD-10PA服务员职位工作描述 HK-JD-11洗衣房主管职位工作描述 HK-JD-12洗衣房客衣服务员职位工作描述 HK-JD-13洗衣房服装洗涤工职位工作描述 HK-JD-14洗衣房服装熨烫工职位工作描述 HK-JD-15洗衣房布草洗涤工职位工作描述 HK-JD-16洗衣房布草熨烫工职位工作描述 HK-JD-17制服房主管职位工作描述

HK-JD-18制服房缝纫工职位工作描述 HK-JD-19制服及布草服务员职位工作描述 管家部简介 管家部是酒店为客人提供住宿服务的部门，由于客房收入是酒店收入的重要来源，因此管家部的经营管理，直接关系到整个酒店的社会效益和经济效益。 管家部由办公室、客房楼层、公共区域清洁、洗衣房、布草房等部分组成。 管家部的主要职能是：为客人提供舒适、安全、洁净、便利的房间环境和热情、周到、快捷的服务。

客房服务员和PA工作职责和工作内容

客房服务员岗位职责： [直系上级]：客房主管、客房领班 [岗位职责]：按标准要求负责清扫整理客房和楼层公共区域，为客人提供干净安全的客房和环境，满足客人的服务需求，负责本区域安全工作。[工作内容]： 1.规范着装，保持良好的仪容仪表，做到“三轻”：说话轻、动作轻、走 路轻。 2.遇见客人微笑和问候，礼貌待客，提供温馨的服务。 3.按照规范流程和质量标准，完成每天所规定的工作。 4.认真如实填写工作报表,发现特殊情况及时反映给主管，并在报表备注上 注明。 5.按照操作标准和消毒要求，清洁消毒、杯具、恭桶等需消毒的物品和设 施。 6.检查退房，按规范处理客人的遗留物品，及时报告上级和前台。 7.做好每天大清洁项目和单项清洁项目。 8.清扫客房和楼层公共区域时发现设施设备的故障和损坏，立即报修。 9.做好楼层客房钥匙的领用、保管和交接工作。 10.中班按要求提供夜间服务，做好楼层和公共区域的清洁工作。 11.及时执行前台的服务指令，满足客人要求，并及时反馈结果。 12.做好布草的收发、盘点、运送及补充，正确使用和保管工作车、保洁工 具、通讯工具和客用品。 13.熟悉酒店医疗服务规定，遇生病客人给予关心和帮助，并立即报告上级。 14.及时满足客人提出的需求，超出职权范围及时报告。 15.树立安全防范意识，发现可疑的人和事，立即报告上级。 16.完成上级指派的其它任务。

公共区域服务员的职责： [直系上级]：客房主管、客房领班 [岗位职责]：负责酒店公共区域的清洁，为客人提供干净、温馨、安全的环境。 满足客人的服务需求。 [工作内容]: 1.规范着装，保持良好的仪容仪表，做到“三轻”：说话轻、动作轻、走 路轻。营造良好环境。 2.遇见客人微笑和问候，礼貌待客，提供温馨的服务。 3.每天按规范流程和质量标准完成酒店门庭、大堂、客厕、员工区域等公 共区域的清洁工作。 4.做好定期的各项清洁工作和公共区域的计划卫生。 5.按照标准实施酒店绿植的清洁养护和准确摆放。 6.打扫公共区域时发现设施设备的故障和损坏及时报修。 7.工作中遇到困难或不能解决的问题，及时报告客房主管或领班。 8.正确使用、保管和保养清洁工具、通讯工具。 9.及时解决客人提出的需求，安抚和处理客人的投诉，超出职权范围，及 时报告。 10.树立安全防范意识，发现可疑的人和事，立即报告上级。 11.完成上级指派的其它任务。 12. . 13. 14.

酒店pa岗位职责

酒店pa主管岗位职责 职位：管事部主管 呈报：管事部经理 职责： 1、在部门经理的领导下，负责部门全面管理及日常工作安排； 2、制定每月工作计划和岗位职责制，操作流程等，并与其它部门沟通协调工作； 3、以身作责贯彻执行各项规章制度，督导、检查各班组的岗位责任制和操作流程的执行落实，并向经理汇报； 4、做好每月上班更期表，做表一定按实际情况编排； 5、记录、报告所有区域的工程问题并检查落实，并向经理汇报； 6、负责本部培训工作，提高员工素质； 7、负责本部每周例会； 8、制订对机器每周维护与保养； 9、控制物品消耗，进行成本控制，跟进每月跟办盘点工作； 10、调配好人手，审批部长和员工的调班和调休申请； 11、定期对下属进行评估，做到有奖有罚，公平合理； 12、检查各班次的交班情况和仓库管理； 13、完成上级安排的其它任务； 管事部PA部长的职责 职位：PA部长 呈报：PA部主管 职责： 1、对经理负责，在主管的直接领导下，认真搞好所辖区区域的卫生清洁工作； 2、加强管理知识及业务知识的学习，熟悉管辖范围内各岗位工作及操作流程； 3、勤巡查，督导下属员工的工作，遇事多请示、汇报；

4、协助主管布置各种盆景、花木摆放、督导花工淋水、施肥、更换及清洁卫生工作； 5、协助主管搞好培训工作； 6、检查下属员工的仪容仪表，签到签退情况； 7、负责组织班前班后会议传达新指示、新任务，安排属下员工的工作分配； 8、定期保养PA的清洁器材； 9、负责各个公共区域工程与维修情况； 10、每天填写清洁卫生检查报告； 11、了解属于员工的思想动向，作好思想工作； 12、完成上级交给其它的工作任务。 管事部PA员的职责 职位：PA员 呈报：PA部长 职责： 1．接受管事主管（部长）的领导，服从管理，严格遵守公司的各项规章制度，按时按质完成上级交办的各项工作任务； 2. 熟练掌握本职业务技能（包括清洁用具的正确使用方法，本岗位的相关卫生标准、工作流程，公司各种房态分布及消费情况等），按要求着装和备好工作用具，及时处理好突发事件后的卫生清洁工作，确保向客人提供一个洁净、优美的消费环境； 3. 维护和保持公共区域以及后勤区域的干净整洁，做好餐具容器等物品的清洗工作，通道抹尘、大理石保养及地毯、沙发等家私设备的清洁工作； 4. 积极参加公司及部门组织召开的各种会议、培训活动、各类企业文化活动、公司要求的加班活动及每周的大扫除活动； 5. 要积极上进，不断加强业务技能、文化知识的学习，进一步提高自身综合素质; 6. 在服务过程中必须同服务员一样使用“晚上好！”、“里面请！”、“请慢走！”等礼貌用语。 7 、向领导汇报丢失，损坏的物品，设备等情况；

PA员工岗位职责[1]1

PA员工岗位职责 1、遵守会所和部门规章制度； 2、服从领班分配的工作和特殊任务； 3、做好工作前的个人卫生准备，如仪容、仪表、工作服、鞋等； 4、负责会所各区域卫生的清洁和保养工作； 5、熟悉各种清洁工具和清洁剂的正确使用方式、方法； 6、任何公共地方内所有拾到的失物及发现任何物品，立刻报告； 7、熟悉大厅地面打蜡、刮玻璃、洗地毯、大厅地面抛光、晶面处理的各项操作规程； 8、定时清倒垃圾，做好物品的清洁，消毒工作车； 9、熟悉各种操作程序，并按程序进行操作； 10、熟悉各班组的操作标准和定期参加部门的培训； 11、负责会所设施的保养和清洁，并作好维修记录； 12、节约会所能源，加强安全防范工作及保护意识； PA行为规范 1.与客人、同事及上司见面时必须使用礼貌用语，如您好、请、谢谢、对不起、请原谅、没关系、再见，在到使用五声（欢迎声、问候声、致谢志、歉意志、欢送声），杜绝四语（否定的语言、烦躁的语言、蔑视的语言） 页脚内容1

2.客人问好，尽量称呼客人的姓氏； 3.主动让路/位给客人，请客人先行； 4.三人以上对话，须用相互都能听得懂的语言； 5.不可询问客人私人问题（如年龄、收入、婚姻）； 6.复述客人要求； 7.不能满足或不明白客人的需求必须立即道歉，同时给客人一个解决的建议或主动协助联系解决，绝对不可以忽视客人的要求； 8.在工作岗位时保持精神饱满，随时留意客人是否需服务。 9.举止要端庄稳重，落落大方，表情自然诚恳，和蔼可亲。 10.双手不得插腰、插入衣裤口袋或随意乱放，不得敲桌子或玩弄其它物品。 11.员工的手势要求规范适度。在向客指示方向时，要将手臂自然前伸（上身稍向倾，以示尊重），手指并拢掌心向下，指向目标，切忌12.用手指或笔杆指点，谈话时手势不宜过多，幅度不宜过大。 13.在客人面前，任何时候不得有以下行为：打喷嚏、打哈欠、伸懒腰、挖耳鼻、剔牙、打饱嗝、挖眼屎、搓泥垢、修指甲、吸烟、吹口哨、哼歌曲等，这是极不礼貌的举止，必须杜绝。 14.在服务区域内，身体不得东倒西歪，前倾后靠，不得伸懒腰、驼背、耸肩。 15.对客人服务时，不得流露出厌烦、冷淡、愤怒、僵硬的表情。 16.在服务、工作、打电话和与客人交谈时，如有客人走近，应立即示意，以表示已注意到他（她）的到来，不得无所表示，等客人先开口。 页脚内容2

酒店管家部岗位职责说明

管家部岗位职责 目录 一.客房(楼层) 1.工作职责描述 行政管家 2页楼层主管 3-4页楼层领班 5-9页楼层服务员 10-13页文员 14页 二.公共区域 1.工作职责描述 PA主管 15页PA领班 16页公区服务员 17页园艺师领班 18页园艺师 19页 三.洗衣房 1.工作职责描述 洗衣房主管 22-23页文员 24页洗衣房领班 25页布草房领班 26页洗衣房服务员 27页布草房领班 28页

工作概述JOB SUMMARY: 负责管家部的全面工作,保证酒店的清洁达到要求。工作职责DUTIES RESPONSIBILITIES: ?制定部门规章制度并贯彻执行。 ?制订部门操作守则及工作程序，维持及提高工作水平。 ?制订部门年度预算。 ?负责培训及监督管家部的所有职员的工作情况，评估工作表现。 ?安排管家部人员工作时间。 ?安排部门各项盘点工作，选择适用于酒店的各种客用物品及清洁用品。?保证酒店所有职员的制服配套及整洁。 ?与各部门密切配合，建立良好工作关系。 ?处理顾客与员工发生的各种纠纷。 ?及时提供清洁及状况良好的房间供前台销售。 ?统筹安排公共区域的清洁卫生及绿化布置。 ?安排制作布置房间鲜花，水果。 ?安排客房的维修及保养。制订清洁时间表。 ?严格控制客用品及清洁用品的消耗，避免浪费。 ?制订及完善员工使用钥匙制度。 ?安排酒店各部门之布草洗涤，监控洗衣房出品质量及成本开支。 ?监督记录处理客人遗留物品。

工作概述JOB SUMMARY: 全面管理楼层各项工作，确保楼层各个服务环节能顺利进行，从而为客人提供优质高效的住宿服务。 工作职责DUTIES RESPONSIBILITIES: ?及时传达行政管家的各项指令并安排、布置、落实。 ?安排、调配员工当值及休假。 ?分配下属具体工作，检查、督促员工实际操作是否符合标准，并确保服务效率和质量。 ?跟办特别团体及贵宾到步的准备工作，迎候重要贵宾到步。 ?每天检查贵宾房，抽查客房及空房，巡查客房楼层公共及后勤地方，确保房间布置、服务和清洁卫生符合标准。 ?确保客房的保养和维修工作。 ?检查楼层主管的交班日志并对存在问题作出处理。 ?协助值班经理处理客人遗留遗失物品、损坏设施或投诉等事件，向行政管家汇报发生的特殊事件。 ?定期召开防火防盗安全会议，确保客房安全。 ?开展员工培训工作，定期评估员工表现，执行奖惩制度。 ?征询客人意见，设法满足客人的服务要求。