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This version published online on December 30, 2003
Endocrinology, doi:10.1210/en.2003-1270
A more recent version of this article appeared on April 1, 2004
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Submitted on September 23, 2003
Accepted on December 23, 2003

A Novel PPARalpha/gamma Dual Agonist Demonstrates Favorable Effects on Lipid Homeostasis

Qiu Guo1*, Soumya P. Sahoo1, Pei-Ran Wang1, Denise P. Milot1, Marc C. Ippolito1, Margaret S. Wu1, Joanne Baffic1, Chhabi Biswas1, Melba Hernandez1, My-Hanh Lam1, Neelam Sharma1, Wei Han1, Linda J. Kelly1, Karen L. MacNaul1, Gaochao Zhou1, Ranjit Desai1, James V. Heck1, Thomas W. Doebber1, Joel P. Berger1, David E. Moller1, Carl P. Sparrow1, Yu-sheng Chao1, and Samuel D. Wright1

1 Departments of Atherosclerosis and Endocrinology, Metabolic Disorders, and Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900

* To whom correspondence should be addressed. E-mail: qiu guo{at}merck.com.

Patients with type 2 diabetes mellitus exhibit hyperglycemia, dyslipidemia as well as a markedly increased incidence of atherosclerotic cardiovascular disease. Here we report the characterization of a novel arylthiazolidinedione capable of lowering both glucose and lipid levels in animal models. This compound, designated TZD18, is a potent agonist with dual human PPAR{alpha}/{gamma} activities. In keeping with its PPAR{gamma} activity, TZD18 caused complete normalization of the elevated glucose in db/db mice and Zucker diabetic fatty rats. TZD18 lowered both cholesterol and triglycerides in hamsters and dogs. TZD18 inhibited cholesterol biosynthesis at steps before mevalonate and reduced hepatic levels of HMG CoA reductase activity. Moreover, TZD18 significantly suppressed gene expression of fatty acid synthesis and induced expression of genes for fatty acid degradation and triglyceride clearance. Studies on 17 additional PPAR{alpha} or PPAR{alpha}/{gamma} agonists showed that lipid lowering in hamsters correlated with the magnitude of hepatic gene expression changes. Importantly, the presence of PPAR{gamma} agonism did not affect the relationship between hepatic gene expression and lipid lowering. Taken together, these data suggest that PPAR{alpha}/{gamma} agonists, such as TZD18, affect lipid homeostasis, leading to an anti-atherogenic plasma lipid profile. Agents with these properties may provide favorable means for treatment of type 2 diabetes and dyslipidemia and for the prevention of atherosclerotic cardiovascular disease.
Key words: hypolipidemia • diabetes • nuclear receptor • hypolipidemic drugs • PPAR{alpha}/{gamma} • TZD




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