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Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor α Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453)

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Metabolic Diseases Chemistry
Metabolic Diseases/Atherosclerosis Biology
§ Lead Evaluation
Preclinical Candidate Optimization
Department of Chemical Synthesis
# Macromolecular Crystallography
Gene Expression and Protein Biochemistry
Bristol-Myers Squibb, Building 13, P.O. Box 5400, Princeton, New Jersey 08543-5400
*To whom correspondence should be addressed. Telephone: 609-818-7123. Fax: 609-818-6810. E-mail: [email protected]
Cite this: J. Med. Chem. 2010, 53, 7, 2854–2864
Publication Date (Web):March 10, 2010
Copyright © 2010 American Chemical Society

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    Abstract Image

    An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) α agonist, with an EC50 of 10 nM for human PPARα and ∼410-fold selectivity vs human PPARγ in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARδ. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARα ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARα in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

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    Protocols and methods of in vitro and in vivo assays, analytical and spectroscopic data for compounds 1232, and X-ray crystallographic data of compounds 12 and 2. This material is available free of charge via the Internet at

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