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The Differential Interactions of Peroxisome Proliferator-Activated Receptor Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities

Departments of Metabolic Disorders (M.E., T.E.A., G.A.C., C.F.W., D.E.M., J.P.B.) and Medicinal Chemistry (B.M., R.T.M., J.W.B., P.T.M., H.B.W.), Merck Research Laboratories, Rahway, New Jersey

Despite their proven antidiabetic efficacy, widespread use of peroxisome proliferator-activated receptor (PPAR) agonists has been limited by adverse cardiovascular effects. To overcome this shortcoming, selective PPAR modulators (SPPARMs) have been identified that have antidiabetic efficacy comparable with full agonists with improved tolerability in preclinical species. The results of structural studies support the proposition that SPPARMs interact with PPAR differently from full agonists, thereby providing a physical basis for their novel activities. Herein, we describe a novel PPAR ligand, SPPARM2. This compound was a partial agonist in a cell-based transcriptional activity assay, with diminished adipogenic activity and an attenuated gene signature in cultured human adipocytes. X-ray cocrystallography studies demonstrated that, unlike rosiglitazone, SPPARM2 did not interact with the Tyr473 residue located within helix 12 of the ligand binding domain (LBD). Instead, SPPARM2 was found to bind to and activate human PPAR in which the Tyr473 residue had been mutated to alanine (hPPARY473A), with potencies similar to those observed with the wild-type receptor (hPPARWT). In additional studies, we found that the intrinsic binding and functional potencies of structurally distinct SPPARMs were not diminished by the Y473A mutation, whereas those of various thiazolidinedione (TZD) and non-TZD PPAR full agonists were reduced in a correlative manner. These results directly demonstrate the important role of Tyr473 in mediating the interaction of full agonists but not SPPARMs with the PPAR LBD, thereby providing a precise molecular determinant for their differing pharmacologies.

Received for publication August 29, 2007.

Accepted for publication October 16, 2007.

Address correspondence to: Dr. Joel P. Berger, RY80N-C31, Merck Research Laboratories, 126 E. Lincoln Ave., Rahway, NJ 07065. E-mail: joel_berger{at}merck.com

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