1. Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs). Part II: Optimization of 4-(pyrrolidin-1-yl)benzonitrile derivatives.
- Author
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Asano M, Hitaka T, Imada T, Yamada M, Morimoto M, Shinohara H, Hara T, Yamaoka M, Santou T, Nakayama M, Imai Y, Habuka N, Yano J, Wilson K, Fujita H, and Hasuoka A
- Subjects
- Anabolic Agents chemistry, Anabolic Agents pharmacokinetics, Anabolic Agents pharmacology, Androgens pharmacokinetics, Animals, Eunuchism drug therapy, Eunuchism metabolism, Humans, Male, Models, Molecular, Muscles drug effects, Muscles metabolism, Nitriles pharmacokinetics, Organ Size drug effects, Prostate drug effects, Prostate metabolism, Pyrrolidines pharmacokinetics, Rats, Androgens chemistry, Androgens pharmacology, Nitriles chemistry, Nitriles pharmacology, Pyrrolidines chemistry, Pyrrolidines pharmacology, Receptors, Androgen metabolism
- Abstract
We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PK) profiles were poor due to low metabolic stability. To improve the PK profiles, we modified the hydroxypyrrolidine and benzonitrile substituents of 4-(pyrrolidin-1-yl)benzonitrile derivative B, which had a comparable potency as that of compound A. This optimization led us to further modifications, which improved metabolic stability while maintaining potent androgen agonistic activity. Among the synthesized compounds, (2S,3S)-2,3-dimethyl-3-hydroxylpyrrolidine derivative 1c exhibited a suitable PK profile and improved metabolic stability. Compound 1c demonstrated significant efficacy in levator ani muscle without increasing the weight of the prostate in an in vivo study. In addition, compound 1c showed agonistic activity in the CNS, which was detected using sexual behavior induction assay., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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