Indanylacetic acids carrying 4-thiazolyl/oxazolyl-phenyl tail groups, a new class of balanced PPAR alpha/gamma/delta triple agonists: Synthesis, SAR and in vivo efficacy

MEDI 377

Joachim Rudolph, joachim.rudolph.b@bayer.com1, Libing Chen1, Dyuti Majumdar1, William H. Bullock1, Michael Burns2, Soongyu Choi1, Thomas Claus2, Fernando E. Dela Cruz2, Michelle Daly2, Frederick J. Ehrgott1, Jeffrey S. Johnson1, James N. Livingston2, Michelle Nophsker1, Robert W. Schoenleber1, Jeffrey Shapiro2, Susan Tomlinson1, Christopher Town3, Ling Yang2, Manami Tsutsumi2, and Xin Ma, xin.ma.b@bayer.com1. (1) Department of Chemistry Research, Bayer Pharmaceuticals Corporation, 400 Morgan Lane, West Haven, CT 06516, (2) Department of Metabolic Disorders Research, Bayer Pharmaceuticals Corporation, 400 Morgan Lane, West Haven, CT 06516, (3) Department of Research Technologies, Bayer Pharmaceuticals Corporation
Compounds that simultaneously activate the three major peroxisome proliferator-activated receptors (PPAR) alpha, gamma, and delta, hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. Previous studies identified the indanylacetic acid moiety as a preferred and tunable PPAR agonist head group. Here we report the synthesis and SAR studies of new aryl tail group derivatives. While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of PPAR alpha and gamma activity required systematic optimization. This effort led to the discovery of 4-thiazolyl/oxazolyl-phenyl derivatives (I) with potent and balanced PPAR alpha/gamma/delta triple agonistic activity. An optimized candidate from this series was found to exhibit excellent ADME properties and superior therapeutic potential compared to established PPAR gamma and alpha, gamma activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while normalizing glucose levels in diabetic rodent models.

 

General Poster Session
7:00 PM-9:00 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006