Discovery And Preclinical Evaluation Of Bms-711939, An Oxybenzylglycine Based Ppar Alpha Selective Agonist

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) alpha agonist, with an EC50 of 4 nM for human PPAR alpha and >1000-fold selectivity vs human PPAR gamma (EC50 = 4.5 mu M) and PPAR delta (EC50 > 100 mu M) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.