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Review

Androgen receptor modulators: a review of recent patents and reports (2012-2018)

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Pages 439-453 | Received 15 Jan 2019, Accepted 10 May 2019, Published online: 19 May 2019

References

  • Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988;240:889−894.
  • Lu NZ, Wardell SE, Burnstein KL, et al. International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev. 2006;58:782–797.
  • Jenster G, van der Korput HA, van Vroonhoven C, et al. Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol. 1991;5:1396–1404.
  • Gao W, Bohl CE, Dalton JT. Chemistry and structural biology of androgen receptor. Chem Rev. 2005;105:3352–3370.
  • Simental JA, Sar M, Lane MV, et al. Transcriptional activation and nuclear targeting signals of the human androgen receptor. J Biol Chem. 1991;266:510–518.
  • Mooradian AD, Morley JE, Korenman SG. Biological actions of androgens. Endocr Rev. 1987;8:1−28.
  • Bagatell CJ, Bremner WJ. Androgens in men; uses and abuses. N Engl J Med. 1996;334:707–714.
  • Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov. 2004;3:950–964.
  • Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol. 2018;465:134–142.
  • Zhang X, Sui Z. Deciphering the selective androgen receptor modulators paradigm. Expert Opin Drug Discov. 2013;8:191–218.
  • Mohler ML, Bohl CE, Jones A, et al. Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem. 2009;52:3597–3617.
  • Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994;63:25–61.
  • Nieschlag E, Behre HM, Nieschlag S. Testosterone: action, deficiency, substitution. Cambridge, UK: Cambridge University Press; 2004.
  • Andriole G, Bruchovsky N, Chung LW, et al. Dihydrotestosterone and the prostate: the scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia. J Urol. 2004;172:1399–1403.
  • Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108:2509–2519.
  • Labrie F, Luu-The V, Labrie C, et al. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev. 2003;24:152–182.
  • Kicman AT. Pharmacology of anabolic steroids. Br J Pharmacol. 2008;154:502–521.
  • Taplin M-E. Androgen receptor: role and novel therapeutic prospects in prostate cancer. Expert Rev Anticancer Ther. 2008;8:1495−508.
  • Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25:276–308.
  • Ross RK, Pike MC, Coetzee GA, et al. Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Cancer Res. 1998;58:4497−504.
  • Akaza H. Combined androgen blockade for prostate cancer: review of efficacy, safety and cost-effectiveness. Cancer Sci. 2011;102:51–56.
  • Neumann F. The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research. Exp Clin Endocrinol Diabetes. 1994;102:1–32.
  • Barradell LB, Faulds D. Cyproterone. A review of its pharmacology and therapeutic efficacy in prostate cancer. Drugs Aging. 1994;5:59–80.
  • Okada K, Oishi K, Yoshida O, et al. Study of the effect of an anti-androgen (Oxendolone) on experimentally induced canine prostatic hyperplasia. Urol Res. 1988;16:67–72.
  • Baker JW, Bachman GL, Schumacher I, et al. Synthesis and bacteriostatic activity of some nitrotrifluoromethylanilides. J Med Chem. 1967;10:93–95.
  • Neri R, Florance K, Koziol P, et al. A biological profile of a nonsteroidal antiandrogen, SCH 13521 (4ʹ-nitro-3ʹ-tri-fluoromethylisobutyranilide). Endocrinology. 1972;91:427–437.
  • Dole EJ, Holdsworth MT. Nilutamide: an antiandrogen for the treatment of prostate cancer. Ann Pharmacother. 1997;31:65–75.
  • Raynaud JP, Bonne C, Moguilewsky M, et al. The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review. Prostate. 1984;5:299–311.
  • Fradet Y. Bicalutamide (Casodex) in the treatment of prostate cancer. Expert Rev Anticancer Ther. 2004;4:37–48.
  • Schellhammer PF. An evaluation of bicalutamide in the treatment of prostate cancer. Expert Opin Pharmacother. 2002;3:1313–1328.
  • Kolvenbag GJCM, Furr BJA, Blackledge GRP. Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity. Prostate Cancer Prostatic Dis. 1998;1:307–314.
  • Seligson AL, Campion BK, Brown JW, et al. Development of fluridil, a topical suppressor of the androgen receptor in androgenetic alopecia. Drug Dev Res. 2003;59:292–306.
  • Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–711.
  • Yap TA, Smith AD, Ferraldeschi R, et al. Drug discovery in advanced prostate cancer: translating biology into therapy. Nat Rev Drug Discov. 2016;15:699–718.
  • Armstrong CM, Gao AC. Drug resistance in castration resistant prostate cancer: resistance mechanisms and emerging treatment strategies. Am J Clin Exp Urol. 2015;3:64–76.
  • Ito Y, Sadar MD. Enzalutamide and blocking androgen receptor in advanced prostate cancer: lessons learnt from the history of drug development of antiandrogens. Res Rep Urol. 2018;10:23–32.
  • Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–790.
  • Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. New Eng J Med. 2012;367:1187–1197.
  • Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012;72:1494–1503.
  • Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. New Eng J Med. 2018;378:1408–1418.
  • Fizazi K, Albiges L, Loriot Y, et al. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer. Expert Rev Anticancer Ther. 2015;15:1007–1017.
  • Fizazi K, Massard C, Bono P, et al. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Lancet Oncol. 2014;15:975–985.
  • Joseph JD, Lu N, Qian J, et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 2013;3:1020–1029.
  • Korpal M, Korn JM, Gao X, et al. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov. 2013;3:1030–1043.
  • Tong Y, Chen C, Wu J, et al. Abstract 614: proxalutamide (GT0918), a potent androgen receptor pathway inhibitor. Cancer Res. 2014;74(19 Suppl):614.
  • Oksala R, Moilanen A, Riikonen R, et al. Discovery and development of ODM-204: a Novel nonsteroidal compound for the treatment of castration-resistant prostate cancer by blocking the androgen receptor and inhibiting CYP17A1. J Steroid Biochem Mol Biol. in press. DOI:10.1016/j.jsbmb.2018.02.004
  • Gomez L, Kovac JR, Lamb DJ. CYP17A1 inhibitors in castration-resistant prostate cancer. Steroids. 2015;95:80–87.
  • TRC253. [cited 2019 May 15]. Available from: http://www.traconpharma.com/trc253.php
  • Dobs AS, Boccia RV, Croot CC, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013;14:335–345.
  • Kim J, Wu D, Hwang DJ, et al. The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators. J Pharmacol Exp Ther. 2005;315:230–239.
  • Trifu V, Tiplica G-S, Naumescu E, et al. Cortexolone 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0.05% cream. Br J Dermatol. 2011;165:177–183.
  • [cited 2019 May 15]. Available from: http://www.cassiopea.com/activities/product-pipeline.aspx
  • Gauthier S, Martel C, Labrie F. Steroid derivatives as pure antagonists of the androgen receptor. J Steroid Biochem Mol Biol. 2012;132:93–104.
  • Mohler ML, Coss CC, Duke CB III, et al. For review of the patents during 2008–2011. Expert Opin Ther Pat. 2012;22:541–565.
  • Substituted hydantoin and thiohydantoin derivatives as androgen receptor antagonists and their preparation. WO 2018009678. 2018.
  • Thiohydantoin androgen receptor antagonists for the treatment of cancer. WO2018009694. 2018.
  • Thiohydantoin androgen receptor (AR) antagonists for the treatment of cancer. WO2018037342. 2018.
  • Preparation of substituted thiohydantoin derivatives as androgen receptor antagonists. WO 2017123542. 2017.
  • Preparation of substituted thioimidazolidinones as androgen receptor antagonists. WO2012119559. 2012.
  • Horoszewicz JS, Leong SS, Kawinski E, et al. LNCaP model of human prostatic carcinoma. Cancer Res. 1983;43:1809–1818.
  • Veldscholte J, Ris-Stalpers C, Kuiper GG, et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun. 1990;173:534–540.
  • Modulators of resistant androgen receptor. WO2014066799. 2014.
  • Substituted 2-thioxo-imidazolidin-4-ones and spiro analogues thereof, active anti-cancer ingredient, pharmaceutical composition, medicinal preparation, method for treating prostate cancer. WO2016007046. 2016.
  • Preparation of non-steroidal antiandrogens and selective androgen receptor modulators containing a pyridyl moiety. WO2015089634. 2015.
  • Spirohydantoin compounds and their use as selective androgen receptor modulators and preparation. WO2013128421. 2013.
  • Preparation of pyrrolo[1,2-b]pyrazol-2-yl-benzonitrile derivatives as selective androgen receptor modulators. WO2013014627. 2013.
  • Korenchuk S, Lehr JE, MClean L, et al. VCaP, a cell-based model system of human prostate cancer. In Vivo. 2001;15:163–168.
  • Preparation of cyclic urea derivatives as androgen receptor antagonists. WO2013084138. 2013.
  • Preparation of oxooxazolidinylbenzonitrile derivatives and analogs for use as selective androgen receptor modulators. WO2012047617. 2012.
  • Hershberger bioassay in rats. A short-term screening assay for (anti)androgenic properties. OECD guidelines for the testing of chemicals. Test No. 441. Paris: OECD Publishing.
  • Oxazolidine-based compound and selective androgen receptor agonist comprising same WO2015163604. 2015.
  • Selective androgen receptor degrader (SARD) ligands and methods of use thereof. WO2016172358. 2016.
  • Selective androgen receptor degrader (SARD) ligands and methods of use thereof. WO2016172330. 2016.
  • Selective androgen receptor degrader (SARD) ligands and methods of use thereof. US20180118663. 2018.
  • Selective androgen receptor degrader (SARD) ligands and methods of use thereof. US20170137374. 2017.
  • Selective androgen receptor degrader (SARD) ligands and methods of use thereof. US20170029370. 2017.
  • Selective androgen receptor degrader (SARD) ligands and methods of use thereof. US20170095446. 2017.
  • Preparation of N-phenyl substituted amides as androgen receptor modulators useful in treating cancer. WO2016079521. 2016.
  • Preparation of N-phenyl substituted amides as androgen receptor modulators and their use as anti-cancer agents. WO2016079522. 2016.
  • Savoie PR, Welch JT. Preparation and utility of organic pentafluorosulfanyl-containing compounds. Chem Rev. 2015;115:1130–1190.
  • Preparation of benzotrifluoride or a related trifluoromethylphenyl compounds as selective androgen receptor modulators. WO2013152170. 2013.
  • Kinoyama I, Taniguchi N, Toyoshima A, et al. (+)-(2R,5S)-4-[4-Cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist. J Med Chem. 2006;49:716–726.
  • Preparation of (2R,5S)-4-(4-cyanophenyl)-2,5-dimethylpiperazine-1-carboxamide derivatives as antagonists for mutated androgen receptor. WO2012053630. 2012.
  • Preparation of novel tetrahydropyridopyrimidine compounds, and antiandrogens and antitumor agents containing them. WO2015182712. 2015.
  • Preparation of condensed pyrimidine compounds as androgen receptor antagonists. WO2017090719. 2017.
  • Preparation of cyclopentyl benzonitrile compounds as selective androgen receptor modulators for therapy. WO2013055577. 2013.
  • Preparation of aminoazole derivatives as androgen receptor modulators. WO2017099237. 2017.
  • Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof. WO2012142208. 2012.
  • Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof. US20140107085. 2014.
  • Adeniji AO, Chen M, Penning TM. AKR1C3 as a target in castrate resistant prostate cancer. J Steroid Biochem Mol Biol. 2013;137:136–149.
  • Carbonitrile derivatives as selective androgen receptor modulators and their preparation. WO2015181676. 2015.
  • Preparation of indolecarbonitriles as selective androgen receptor modulators. WO2014013309. 2014.
  • Preparation of quinolinyloxycyclohexylmethylheteroarylcarboxamide derivatives for use as androgen receptor antagonists. WO2014001247. 2014.
  • Preparation of 4,5-dihydroisoxazoles and 4,5-dihydro[1,2,4]-oxadiazoles as androgen receptor modulators. WO2013057372. 2013.
  • Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310:644–648.
  • Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.
  • Magee JA, Chang L-W, Stormo GD, et al. Direct, androgen receptor-mediated regulation of the FKBP5 gene via a distal enhancer element. Endocrinology. 2006;147:590–598.
  • Preparation of heteroaryl carboxamides as androgen receptor modulators. WO2012143599. 2012.
  • Singh RP, Agarwal R. Mechanisms of action of novel agents for prostate cancer chemoprevention. Endocr Relat Cancer. 2006;13:751–778.
  • Teiten M-H, Gaascht F, Eifes S, et al. Chemopreventive potential of curcumin in prostate cancer. Genes Nutr. 2010;5:61–74.
  • Compounds with (1E,6E)-1,7-bis(3,4-dimethoxyphenyl)-4,4-disubstituted-hepta-1,6-diene-3,5-dione structural scaffold, their biological activity and preparation. WO2013192091. 2013.
  • Sramkoski RM, Pretlow TG 2nd, Giaconia JM, et al. A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim. 1999;35:403–409.
  • Wilson V, Bobseine K, Lambright C, et al. A novel cell line, MDA-kb2, that stably expresses an androgen- and glucocorticoid-responsive reporter for the detection of hormone receptor agonists and antagonists. Toxicol Sci. 2002;66:69–81.
  • Novel androgen receptor antagonist containing polycyclic amide or sulfonamide compound, and pharmaceutical preparation and prostatic cancer treatment agent containing the antagonist. WO2013128927. 2013.
  • Yamada A, Fujii S, Mori S, et al. Design and synthesis of 4-(4-benzoylaminophenoxy)phenol derivatives as androgen receptor antagonists. ACS Med Chem Lett. 2013;4:937–941.
  • Andersen RJ, Mawji NR, Wang J, et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell. 2010;17:535–546.
  • Preparation of aziridine bisphenol ethers as androgen receptor modulators useful in the treatment of cancer. US20130336962. 2013.
  • Fluorinated bisphenol ether compounds and methods for their use. US20130045204. 2013.
  • Preparation of ester derivatives of bisphenol-related compounds as androgen receptor modulators. WO2014179867. 2014.
  • Preparation of bisphenol ether compounds with novel bridging groups and methods for their use. US20150010469. 2015.
  • Preparation of bisphenol derivatives and their use as androgen receptor activity modulators. WO2017177307. 2017.
  • Preparation of pyrrolidone derivatives as androgen receptor modulators and methods for their use in therapy. WO2015184393. 2015.
  • Banuelos CA, Tavakoli I, Tien AH, et al. Sintokamide A is a novel antagonist of androgen receptor that uniquely binds activation function-1 in its amino-terminal domain. J Biol Chem. 2016;291:22231–22243.
  • Preparation of diaryl(alkyl)ketones as androgen receptor N-terminal domain inhibitors for the treatment of cancer. WO2018136792. 2018
  • Androgen receptor antagonists. WO2017041040. 2017.
  • Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017;16:101–114.
  • Toure M, Crews CM. Small-molecule PROTACS: new approaches to protein degradation. Angew Chem Int Ed. 2016;55:1966–1973.
  • Sakamoto KM, Kim KB, Verma R, et al. Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol Cell Proteomics. 2003;2:1350–1358.
  • Schneekloth JS Jr, Fonseca FN, Koldobskiy M, et al. Chemical genetic control of protein levels: selective in vivo targeted degradation. J Am Chem Soc. 2004;126:3748–3754.
  • Lisztwan J, Imbert G, Wirbelauer C, et al. The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev. 1999;13:1822–1833.
  • Buckley DL, Van Molle I, Gareiss PC, et al. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction. J Am Chem Soc. 2012;134:4465–4468.
  • Compounds and methods for the targeted degradation of the androgen receptor. WO2016118666. 2016.
  • Compounds and methods for the targeted degradation of androgen receptor. US20170327469. 2017.
  • Lopez-Girona A, Mendy D, Ito T, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012;26:2326–2335.
  • Compounds and methods for the targeted degradation of androgen receptor. US20180099940. 2018.

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