title: Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity.
abstract: Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. The small-molecule FABP4 inhibitor BMS309403 was previously reported to improve insulin sensitivity in leptin-deficient Lep(ob)/Lep(ob) (ob/ob) mice. However, this compound was not extensively characterized in the more physiologically relevant animal model of mice with diet-induced obesity (DIO). Here, we report the discovery and characterization of a novel series of FABP4/5 dual inhibitors represented by Compounds 1-3. Compared with BMS309403, the compounds had significant in vitro potency toward both FABP4 and FABP5. In cell-based assays, Compounds 2 and 3 were more potent than BMS309403 to inhibit lipolysis in 3T3-L1 adipocytes and in primary human adipocytes. They also inhibited MCP-1 release from THP-1 macrophages as well as from primary human macrophages. When chronically administered to DIO mice, BMS309403 and Compound 3 reduced plasma triglyceride and free FA levels. Compound 3 reduced plasma free FAs at a lower dose level than BMS309403. However, no significant change was observed in insulin, glucose, or glucose tolerance. Our results indicate that the FABP4/5 inhibitors ameliorate dyslipidemia but not insulin resistance in DIO mice.
authors.affiliation: Department of Diabetes & Obesity Research, Merck Research Laboratories, Kenilworth, NJ 07033, USA. hong.lan@merck.com
authors.forename: Hong
authors.initials: H
authors.lastname: Lan
authors.forename: Cliff C
authors.initials: CC
authors.lastname: Cheng
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kowalski
authors.forename: Ling
authors.initials: L
authors.lastname: Pang
authors.forename: Lixin
authors.initials: L
authors.lastname: Shan
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chuang
authors.forename: James
authors.initials: J
authors.lastname: Jackson
authors.forename: Alberto
authors.initials: A
authors.lastname: Rojas-Triana
authors.forename: Loretta
authors.initials: L
authors.lastname: Bober
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Johannes
authors.initials: J
authors.lastname: Voigt
authors.forename: Peter
authors.initials: P
authors.lastname: Orth
authors.forename: Xianshu
authors.initials: X
authors.lastname: Yang
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Shipps
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hedrick
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D050171:Dyslipidemias / Q000139:chemically induced / Q000188:drug therapy; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008066:Lipolysis / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy*; D014280:Triglycerides / Q000097:blood
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004041:Dietary Fats; C493411:Fabp4 protein, mouse; C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; D000960:Hypolipidemic Agents; D009363:Neoplasm Proteins; D014280:Triglycerides