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.
Yan Shi  1 ,  Jun Li  1 ,  Lawrence J Kennedy  1 ,  Shiwei Tao  1 ,  Andrés S Hernández  1 ,  Zhi Lai  1 ,  Sean Chen  1 ,  Henry Wong  1 ,  Juliang Zhu  1 ,  Ashok Trehan  1 ,  Ngiap-Kie Lim  1 ,  Huiping Zhang  1 ,  Bang-Chi Chen  1 ,  Kenneth T Locke  1 ,  Kevin M O'Malley  1 ,  Litao Zhang  1 ,  Rai Ajit Srivastava  1 ,  Bowman Miao  1 ,  Daniel S Meyers  1 ,  Hossain Monshizadegan  1 ,  Debra Search  1 ,  Denise Grimm  1 ,  Rongan Zhang  1 ,  Thomas Harrity  1 ,  Lori K Kunselman  1 ,  Michael Cap  1 ,  Jodi Muckelbauer  1 ,  Chiehying Chang  1 ,  Stanley R Krystek  1 ,  Yi-Xin Li  1 ,  Vinayak Hosagrahara  1 ,  Lisa Zhang  1 ,  Pathanjali Kadiyala  1 ,  Carrie Xu  1 ,  Michael A Blanar  1 ,  Robert Zahler  1 ,  Ranjan Mukherjee  1 ,  Peter T W Cheng  1 ,  Joseph A Tino  1
Affiliations
  • 1. Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
PMID: 27326332 DOI: 10.1021/acsmedchemlett.6b00033
Abstract

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.
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