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.
Highlights
Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages
According to the published values, this compound appeared to be ف30-fold weaker than BMS309403, yet it bound to FABP4 in X-ray crystallography, and in cell-based assays, HTS01037 inhibited lipolysis in 3T3-L1 adipocytes and reduced lipopolysaccharide (LPS)-stimulated inflammation in mouse macrophages [17]
We focused our efforts on building structure-activity relationship (SAR) and increasing affinity for FABP4 while maintaining a у10-fold selectivity window over FABP3 in the temperature-dependent fluorescence (TdF) binding assay and preserving or improving the potency toward FABP5 in the fluorescence polarization (FP) assay
Summary
Fatty acid binding protein-4 (FABP4) and FABP5 are two closely related FA binding proteins expressed primarily in adipose tissue and/or macrophages. According to the published values, this compound appeared to be ف30-fold weaker than BMS309403, yet it bound to FABP4 in X-ray crystallography, and in cell-based assays, HTS01037 inhibited lipolysis in 3T3-L1 adipocytes and reduced lipopolysaccharide (LPS)-stimulated inflammation in mouse macrophages [17]. Interesting compounds were subjected to cell-based assays to evaluate their ability to inhibit lipolysis in mouse 3T3-L1 adipocytes and MCP-1 secretion from THP-1, a human macrophage cell line.
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