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Molecular Pharmacology Fast Forward
First published on October 8, 2004; DOI: 10.1124/mol.104.005553

0026-895X/05/6701-69-77$20.00
Mol Pharmacol 67:69-77, 2005

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Ertiprotafib Improves Glycemic Control and Lowers Lipids via Multiple Mechanisms

David V. Erbe, Suyue Wang, Yan-Ling Zhang, Kimberly Harding, Leslie Kung, May Tam, Leslie Stolz, Yuzhe Xing, Sarah Furey, Ariful Qadri, Lori D. Klaman, and James F. Tobin

Wyeth Research, Cardiovascular and Metabolic Diseases, Cambridge, Massachusetts

Ertiprotafib belongs to a novel class of insulin sensitizers developed for treatment of type 2 diabetes. In insulin-resistant rodent models, ertiprotafib and a close analog lowered both fasting blood glucose and insulin levels and improved glycemic excursion during an oral glucose tolerance test. In addition, treatment of rodents improved lipid profiles, with significantly lowered triglyceride and free fatty acid levels. These results suggested that this therapeutic activity might involve mechanisms in addition to PTP1b inhibition. In this study, we demonstrate that ertiprotafib activates peroxisome proliferator-activated receptor (PPAR){alpha} and PPAR{gamma} at concentrations comparable with those of known agonists of these regulators. Furthermore, it is able to drive adipocyte differentiation of C3H10T1/2 cells, a hallmark of PPAR{gamma} activation. Livers from ertiprotafib-treated animals showed significant induction of acyl-CoA oxidase activity, probably caused by PPAR{alpha} engagement in these animals. We also show that ertiprotafib inhibits PTP1b in vitro with nonclassic kinetics at concentrations above its EC50 for PPAR agonism. Thus, the complete mechanism of action for ertiprotafib and related compounds in vivo may involve multiple independent mechanisms, including (but not necessarily limited to) PTP1b inhibition and dual PPAR{alpha}/PPAR{gamma} agonism. Ertiprotafib pharmacology and interpretation of clinical results must be seen in light of this complexity.

Received July 28, 2004; accepted October 7, 2004

Address correspondence to: David V. Erbe, Wyeth Research, Cardiovascular and Metabolic Diseases, 200 Cambridge Park Drive, Cambridge MA 02140. E-mail: derbe{at}wyeth.com






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