Bioorganic and Medicinal Chemistry p. 3330 - 3349 (2017)
Update date:2022-08-15
Topics:
Aikawa, Katsuji
Asano, Moriteru
Ono, Koji
Habuka, Noriyuki
Yano, Jason
Wilson, Keith
Fujita, Hisashi
Kandori, Hitoshi
Hara, Takahito
Morimoto, Megumi
Santou, Takashi
Yamaoka, Masuo
Nakayama, Masaharu
Hasuoka, Atsushi
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.
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