期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 13, 页码 3330-3349出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.04.018
关键词
Androgen receptor; AR; Selective androgen receptor modulators (SARMs); Testosterone; Hershberger assay; Sexual behavior
We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative lb 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-ethyl3-hydroxy-5-oxopyrrolidin-l-y1]-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. (C) 2017 Elsevier Ltd. All rights reserved.
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