in vivo
BMS-309403 sodium (15 mg/kg; chronic treatment; daily for 6 weeks) improves endothelial function, phosphorylated and total eNOS and reduced plasma triglyceride levels but did not affect endothelium-independent relaxations
Description
BMS 309403 is a potent and selective fatty acid binding protein 4, adipocyte (FABP4) inhibitor (Ki values are <2, 250 and 350 nM for FABP4, FABP3 and FABP5 respectively). Decreases fatty acid uptake in adipocytes in vitro and reduces atherosclerotic lesion area in a mouse model of atherosclerosis. Reduces blood glucose levels and increases insulin sensitivity in a mouse model of obesity.
Uses
FABP4 Inhibitor is a cell-permeable biphenylazolo-oxyacetate that acts as a potent and selective inhibitor of A-FABP (adipocyte Fatty-Acid-Binding Protein) by targeting its fatty acid-binding pocket (Ki = < 2 nM in a competitive binding assay using 1,8-ANS), while exhibiting much lower affinity for muscle and epidermal FABP''s (Ki = 250 nM and 350 nM, respectively).
Biochem/physiol Actions
BMS-309403 is a potent and selective inhibitor of fatty acid binding protein 4 (FABP4), also known as adipocyte FABP (A-FABP, aP2). FABP4 is an intracellular lipid-binding protein responsible for the transportation of fatty acids. It is expressed primarily in adipose tissue and is associated with inflammation, obesity, diabetes and cardiovascular diseases. BMS309403 interacts with the fatty-acid-binding pocket within the interior of FABP4 and has been shown to competitively inhibit fatty acid binding with a Ki value < 2 nM. BMS309403 is orally active and has been shown to reduce atherosclerosis in mice studies.
in vitro
Treatment with BMS-309403 significantly decreased MCP-1 production from THP-1 macrophages in a dose- and time-dependent manner.
References
1) Furuhashi?et al.?(2007),?Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2; Nature?447?959
2) Sulsky?et al. (2007),?Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP); Bioorg. Med. Chem. Lett.,?17?3511
3) Lin?et al.?(2012),?BMS309403 stimulates glucose uptake in myotubes through activation of AMP-activated protein kinase; PLoS One,?7?e44570
4) Bosquet?et al.?(2018),?FABP4 inhibitor BMS3409403 decreases saturated-fatty-acid-induced endoplasmic reticulum stress-associated inflammation in skeletal muscle by reducing p38 MAPK activation; Biochim. Biophys. Acta Mol. Cell Biol. Lipids,?1863?604
5) Gongl?et al. (2018),?FABP4 inhibitors suppress inflammation and oxidative stress in murine and cell models of acute lung injury; Biochem. Biophys. Res. Commun.,?496?1115
