1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators

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• 作者：Eugene L. Piatnitski Chekler ; Rayomond Unwalla ; Taukeer A. Khan ; Raghuram S. Tangirala ; Mark Johnson ; Michael St. Andre ; James T. Anderson ; Thomas Kenney ; Sue Chiparri ; Chris McNally ; Edward Kilbourne ; Catherine Thompson ; Sunil Nagpal ; Gregory Weber ; Scott Schelling ; Jane Owens ; Carl A. Morris ; Dennis Powell ; Patrick R. Verhoest ; Adam M. Gilbert
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2462-2471
• 全文大小：461K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

We present a novel series of selective androgen receptor modulators (SARMs) which shows excellent biological activity and physical properties. 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)-indoline-4-carbonitriles showed potent binding to the androgen receptor (AR) and activated AR-mediated transcription in vitro. Representative compounds demonstrated diminished activity in promoting the intramolecular interaction between the AR carboxyl (C) and amino (N) termini. This N/C-termini interaction is a biomarker assay for the undesired androgenic responses in vivo. In orchidectomized rats, daily administration of a lead compound from this series showed anabolic activity by increasing levator ani muscle weight. Importantly, minimal androgenic effects (increased tissue weights) were observed in the prostate and seminal vesicles, along with minimal repression of circulating luteinizing hormone (LH) levels and no change in the lipid and triglyceride levels. This lead compound completed a two week rat toxicology study, and was well tolerated at doses up to 100 mg/kg/day, the highest dose tested, for 14 consecutive days.