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Selective Modulator
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
Address all correspondence and requests for reprints to: Joel Berger, RY80N-C31, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey 07065. E-mail: joel_berger{at}merck.com.
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.
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|
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|
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|
|
 |
|
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|
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|
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|
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