Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 1; pp. 70 - 83
• Main Authors: Yamamoto, Satoshi, Kobayashi, Hiromi, Kaku, Tomohiro, Aikawa, Katsuji, Hara, Takahito, Yamaoka, Masuo, Kanzaki, Naoyuki, Hasuoka, Atsushi, Baba, Atsuo, Ito, Mitsuhiro
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-01-2013
• Subjects: 3-Aryl-3-hydroxy-1-phenylpyrrolidine derivatives; amides; Androgen receptor antagonists; Androgen Receptor Antagonists - chemistry; Androgen Receptor Antagonists - therapeutic use; Androgen receptors; Animal models; Animals; Antagonists; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Antitumor activity; binding capacity; Castration; Castration-resistant prostate cancers; Cell culture; Cell Line, Tumor; chemistry; Drug Design; Humans; Male; Mice; Models, Molecular; Prostate - drug effects; Prostate - metabolism; Prostate - surgery; Prostate cancer; prostatic neoplasms; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - surgery; Pyrrolidines - chemistry; Pyrrolidines - therapeutic use; Receptors, Androgen - metabolism; Tumors; Xenograft Model Antitumor Assays; Xenografts; AR; DHT; PC; CAB; SAR; EDC; Castration-resistant prostate cancers; CRPC; Androgen receptor antagonists; PSA; 3-Aryl-3-hydroxy-1-phenylpyrrolidine derivatives
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.11.001

A series of 3-aryl-3-hydroxy-1-phenylpyrrolidine compounds were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers.
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 (R2) 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 (R1) 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.