Benzoxazepinones: The discovery of a novel SARM template

MEDI 239

Stephen Rafferty, swr78127@gsk.com1, Robert Gampe2, Bajin Han2, Sab A. Randhawa, Sab.A.Randhawa@gsk.com3, Eugene L. Stewart, Eugene.L.Stewart@gsk.com4, and Christopher M. Yates2. (1) Molecular Discovery Research-Discovery Medicinal Chemistry, GlaxoSmithKline, Five Moore Dr, P.O. Box 13398, Research Triangle Park, NC 27709, (2) GlaxoSmithKline, (3) Medicinal Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, (4) Computational, Analytical, and Structural Sciences, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709
Nuclear receptors (NRs) are a class of structurally related proteins that modulate gene expression by acting as ligand-dependent transcription factors. The steroid receptors, for example, the androgen receptor (AR), represent a subclass of the nuclear receptor superfamily. The terms Selective Androgen Receptor Modulator (SARM) refers to an AR ligand which functions as an agonist in some tissues (e.g. muscle), while having no effect or even an antagonist effect in other tissues (e.g. prostate). An ideal SARM has all the beneficial effects of endogenous androgens, while sparing sexual accessory organs, specifically the prostate. It is this avenue on which our group chose to focus in the search for non-steroidal SARMs. The synthetic design, SAR, and in vivo studies for the benzoxazepinone series (shown below) will be presented, with the in vivo data categorizing this series as a true AR modulator: anabolic effect (muscle growth) without prostate stimulation.

 

General Oral Session
1:30 PM-4:50 PM, Tuesday, August 21, 2007 BCEC -- 210A, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007