1. Academic Validation
  2. Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications

Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications

  • J Med Chem. 2007 Jun 28;50(13):3015-25. doi: 10.1021/jm070312d.
James J Li 1 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 Beehler Gary J Grover Aberra Fura Viral P Vyas Cindy Y Li Jack Z Gougoutas Michael A Galella Robert Zahler Jacek Ostrowski Lawrence G Hamann
Affiliations

Affiliation

  • 1 Discovery Chemistry, Computer Assisted Drug Design, Metabolic Disease Research, Metabolism and Pharmacokinetics, Discovery Analytical Sciences, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. James.Li@bms.com
Abstract

A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective Androgen Receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in Androgen Receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/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 are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.

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