2. Academic Validation
  3. Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist

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

Affiliation

  • 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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