Small Molecule Dual FABP4/5 Inhibitors Ameliorate Dyslipidemia in Mice with Diet-Induced Obesity | American Diabetes Association
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Small Molecule Dual FABP4/5 Inhibitors Ameliorate Dyslipidemia in Mice with Diet-Induced Obesity FABP4 and FABP5 are two closel FABP4 and FABP5 are two closely related fatty acid binding proteins expressed primarily in adipose tissue and macrophage. Mice with double deletion of Fabp4 and Fabp5 genes are resistant to diet-induced obesity (DIO), dyslipidemia, insulin resistance and type 2 diabetes. A small molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lepob/Lepob (ob/ob) mice. However, the compound was not extensively characterized in the more physiologically relevant DIO mice. Here, we report the discovery of a novel series of FABP4/5 dual inhibitors, represented by Compounds 1-3. These compounds are triazolopyrimidine derivatives without a carboxylic acid moiety. Compared with BMS309403, the compounds had significant in vitro potency towards both FABP4 and FABP5. In cell-based assays, BMS309403 and Compounds 2, 3 inhibited basal and isoproterenol-stimulated lipolysis in 3T3 L1 adipocytes and in primary human adipocytes, with the dual inhibitors being slightly more potent. They also inhibited basal and lipopolysaccharide (LPS)-stimulated MCP-1 release from THP-1 macrophage and primary human macrophage. When chronically administered to DIO mice, BMS309403 or Compound 3 reduced plasma triglyceride and free fatty acid levels, but no significant change was observed on insulin, glucose or glucose tolerance. Compound 3 reduced plasma free fatty acids at all three dose levels (3 mg/kg, 10 mg/kg and 30 mg/kg), while the effect of BMS309403 was only observed at 30 mg/kg. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia in DIO mice, and that dual FABP4/5 inhibition appears to be more effective than selective FABP4 inhibition. HONG LAN, CLIFF C. CHENG, TIMOTHY J. KOWALSKI, LING PANG, LIXIN SHAN, CHENG-CHI CHUANG, JAMES JACKSON, ALBERTO ROJAS-TRIANA1, LORETTA BOBER, LI LIU, JOHANNES VOIGT, PETER ORTH, XIANSHU YANG, GERALD W. SHIPPS, JOSEPH A. HEDRICK 685-P Kenilworth, NJ, Cambridge, MA Diabetic Dyslipidemia
71st Scientific Sessions (2011)
Diabetic Dyslipidemia