Discovery of Potent, Orally-Active, and Muscle-Selective Androgen Receptor Modulators Based on anN-Aryl-hydroxybicyclohydantoin Scaffold^†

A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited > 50-fold selectivity for muscle over prostate.