title: Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists.
abstract: We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R(2)) of the pyrrolidine ring increased the AR binding affinity. The (2S,3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R(1)) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. satoshi.yamamoto@takeda.com
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaku
authors.forename: Katsuji
authors.initials: K
authors.lastname: Aikawa
authors.forename: Takahito
authors.initials: T
authors.lastname: Hara
authors.forename: Masuo
authors.initials: M
authors.lastname: Yamaoka
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hasuoka
authors.forename: Atsuo
authors.initials: A
authors.lastname: Baba
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Ito
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use*; D002369:Castration; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D011759:Pyrrolidines / Q000737:chemistry* / Q000627:therapeutic use*; D011944:Receptors, Androgen / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D011759:Pyrrolidines; D011944:Receptors, Androgen