Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist

ACS Med Chem Lett. 2016 Apr 4;7(6):590-4. doi: 10.1021/acsmedchemlett.6b00033. eCollection 2016 Jun 9.


BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 μM) and PPARδ (EC50 > 100 μM) 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.

Keywords: Peroxisome proliferator-activated receptor (PPAR) α selective agonist; high fat fed hamster model; human ApoA1 transgenic mice; pharmacokinetics.