5V8Q

Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs): Part III

5V8Q の概要

• エントリーDOI: 10.2210/pdb5v8q/pdb
• 分子名称: Androgen receptor, GLYCEROL, 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile, ... (4 entities in total)
• 機能のキーワード: androgen receptor, selective androgen receptor modulators, sarms, signaling protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P10275
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29562.51

構造登録者

Wilson, K.P. (登録日: 2017-03-22, 公開日: 2017-05-24, 最終更新日: 2024-10-30)

主引用文献

Aikawa, K.,Asano, M.,Ono, K.,Habuka, N.,Yano, J.,Wilson, K.,Fujita, H.,Kandori, H.,Hara, T.,Morimoto, M.,Santou, T.,Yamaoka, M.,Nakayama, M.,Hasuoka, A.
Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs) Part III: Discovery of 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2f as a clinical candidate.
Bioorg. Med. Chem., 25:3330-3349, 2017

PubMed Abstract: We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR.

PubMed: 28454849
DOI: 10.1016/j.bmc.2017.04.018

実験手法

X-RAY DIFFRACTION (1.44 Å)