Discovery of Potent and Muscle Selective Androgen Receptor Modulators through Scaffold Modifications

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• 作者：James J. Li ; James C. Sutton ; Alexandra Nirschl ; Yan Zou ; Haixia Wang ; Chongqing Sun ; Zulan Pi ; Rebecca Johnson ; Stanley R. Krystek ; Jr. ; Ramakrishna Seethala ; Rajasree Golla ; Paul G. Sleph ; Blake C.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：June 28, 2007
• 年：2007
• 卷：50
• 期：13
• 页码：3015 - 3025
• 全文大小：278K
• 年卷期：v.50,no.13(June 28, 2007)
• ISSN：1520-4804

文摘

A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscleselective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitropotency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the leadcompound 11a (AR K_i = 0.9 nM, EC₅₀ = 1.8 nM) for 14 days induced muscle growth with an ED₅₀ of 0.09mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model.Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65%and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series areexpected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.