Indanylacetic Acid Derivatives Carrying 4-Thiazolyl-phenoxy Tail Groups, a New Class of Potent PPAR /http://pubs.acs.org/i

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• 作者：Joachim Rudolph ; Libing Chen ; Dyuti Majumdar ; William H. Bullock ; Michael Burns ; Thomas Claus ; Fernando E. Dela Cruz ; Michelle Daly ; Frederick J. Ehrgott ; Jeffrey S. Johnson ; James N. Livingston ; Robe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：March 8, 2007
• 年：2007
• 卷：50
• 期：5
• 页码：984 - 1000
• 全文大小：298K
• 年卷期：v.50,no.5(March 8, 2007)
• ISSN：1520-4804

文摘

Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypesalpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditionsassociated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moietyas a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship(SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists.While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement ofPPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were notknown in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivativeswith potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was foundto exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gammaactivating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, whilenormalizing glucose levels in diabetic rodent models.