期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 9, 页码 1897-1901出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.03.038
关键词
Androgen receptor; Selective androgen receptor modulators (SARMs); 4-(Pyrrolidin-1-yl)benzonitrile; Pharmacokinetics (PK); Liver microsomal metabolic stability
资金
- National Institutes of Health, National Institute of General Medical Sciences
- Howard Hughes Medical Institute
- U.S. Department of Energy [DE-AC02-05CH11231]
We recently reported a class of novel tissue-selective androgen receptor modulators (SARMs), represented by a naphthalene derivative A. However, their pharmacokinetic (PR) 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 is exhibited a suitable PR profile and improved metabolic stability. Compound is 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. (C) 2017 Elsevier Ltd. All rights reserved.
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