Distinct Properties and Advantages of a Novel Peroxisome Proliferator-Activated Protein Selective Modulator

JOEL P. BERGER, ANN E. PETRO, KAREN L. MACNAUL, LINDA J. KELLY, BEI B. ZHANG, KAREN RICHARDS, ALEX ELBRECHT, BRUCE A. JOHNSON, GAOCHAO ZHOU, THOMAS W. DOEBBER, CHHABI BISWAS, MONA PARIKH, NEELAM SHARMA, MICHAEL R. TANEN, G. MARIE THOMPSON, JOHN VENTRE, ALAN D. ADAMS, RALPH MOSLEY, RICHARD S. SURWIT, AND DAVID E. MOLLER Departments of Metabolic Disorders (J.P.B., K.L.M., L.J.K., B.B.Z., G.Z., T.W.D., C.B., N.S., M.R.T., G.M.T., J.V., D.E.M.), Medicinal Chemistry (B.A.J., A.D.A., R.M.) and Bioinformatics (A.E.), Merck Research Laboratories, Rahway, New Jersey 07065; Department of Drug Metabolism (K.R., M.P.), Merck Research Laboratories, West Point, Pennsylvania 19486; and Department of Psychiatry and Behavioral Sciences (A.E.P., R.S.S.), Duke University Medical Center, Duke University, Durham, North Carolina 27710  

Antidiabetic thiazolidinediones (TZDs) and non- TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor _ (PPAR_). Here, we report the identification and characterization of a novel non-TZD selective PPAR_ modulator (nTZDpa). nTZDpa bound potently to PPAR_ with high selectivity vs. PPAR_ or PPAR_. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPAR_ partial agonist and was able to antagonize the activity of PPAR_ full agonists.

nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPAR_ conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPAR_ full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia.

However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPAR_ target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPAR_ modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome. (Molecular Endocrinology 17: 662-676, 2003)

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