Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 7, Pages 2854-2864Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm9016812
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An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC50 of 10 nM for human PPAR alpha and similar to 410-fold selectivity vs human PPAR gamma 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 PPAR delta. 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 PPAR alpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR alpha in the development of the SA R that ultimately resulted in the discovery of compound 2 is discussed.
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