BMS 309403

BMS309403 is specifically designed to target FABP4 with a Ki value less than 2 nM. It is a potent and selective FABP4 inhibitor.[1]

Fatty acid binding proteins (FABPs) are small-molecular weight hydrophobic proteins containing a large hydrophobic cavity, into which naturally occurring long-chain fatty acids and synthetic hydrophobic ligands can be accepted. FABPs act as transporters of endogenous fatty acids from the cell surface to various sites of fatty acid storage and metabolism. In addition to the roles of FABP4 in regulating lipid metabolism and insulin sensitivity, recent pharmacological and biological findings have indicated a regulatory function of FABP4 in inflammation. FABP4 is expressed mainly to macrophages and inflammatory response[1,2]

BMS309403 is an aromatic biphenyl azol compound that competes with fatty acids for the binding pocket of A-FABP with high specificity. BMs30940323 has been shown to lower Mcp-1 secretion from thp-1 macrophages.[3,4]

Chronic administration of BMS309403 (15 mg/kg/day; from 12 to 18 weeks of age) in ApoE-/-mice significantly improved therelaxations, maximal relaxation and EC50 to UK14304, acetylcholine and A23187. Mice orally BMS309403 significantly increased glucose uptake in myotubes in a time and dose dependent manner. Administered with BMS309403 are effectively protected against severe atherosclerosis and type 2 diabetes.[3,4]

References:
[1]Okada T, Hiromura M, Otsuka M etal. , Synthesis of BMS-309403-related compounds, including [¹⁴C]BMS-309403, a radioligand for adipocyte fatty acid binding protein. Chem Pharm Bull (Tokyo). 2012;60(1):164-8.
[2]Suhre K, Römisch-Margl W, de Angelis MH etal. , Identification of a potential biomarker for FABP4 inhibition: the power of lipidomics in preclinical drug testing. J Biomol Screen. 2011 Jun;16(5):467-75
[3] Lin W1, Huang X, Zhang Letal. , BMS309403 stimulates glucose uptake in myotubes through activation of AMP-activated protein kinase. PLoS One. 2012;7(8):e44570.
[4] Lee MY, Li H, Xiao Y, Zhou Z, Xu A, Vanhoutte PM.   Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells. Br J Pharmacol. 2011 Apr;162(7):1564-76.

Synthesis of BMS-309403-related compounds, including [(1)(4)C]BMS-309403, a radioligand for adipocyte fatty acid binding protein.[Pubmed:22223390]

Chem Pharm Bull (Tokyo). 2012;60(1):164-8.

Adipocyte fatty acid binding protein (A-FABP; FABP4), which is predominantly expressed in macrophages and adipose tissue, regulates fatty acid storage and lipolysis, and is also an important mediator of inflammation. Here, we report a synthesis of (14)C-labeled 2-[2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy]acetic acid (BMS309403), a potent and selective small-molecular FABP4 inhibitor, as a chemical tool for investigating the roles of FABP4 in inflammatory and metabolic disorders. The structure-activity relationship of several BMS derivatives for inhibition of FABP4 is also reported.

Effect of fill weight, capsule shell, and sinker design on the dissolution behavior of capsule formulations of a weak acid drug candidate BMS-309403.[Pubmed:14601962]

Pharm Dev Technol. 2003;8(4):379-83.

Two strengths of BMS-309403 capsules were developed from a common stock granulation. Dissolution testing of the capsules was conducted utilizing the USP apparatus 2 (paddle) with a neutral pH dissolution medium. Unexpectedly, the lower-strength capsules exhibited slower dissolution than the higher-strength capsules filled with the same stock granulation. Higher variability was also observed for the lower-strength capsules. This was found to be mainly caused by a low fill weight in a relatively large size hard gelatin capsule shell. Instead of bursting open, some gelatin capsule shells softened and collapsed onto the granulation, which delayed the release of the active drug. The problem was aggravated by the use of coil sinkers which hindered the medium flow around the capsules. Switching from the gelatin capsule shells to the HPMC (hydroxypropyl methylcellulose) shells reversed the dissolution rate ranking between the two capsule strengths. However, both dissolved at a slower rate initially than the gelatin capsules due to the inherent dissolution rate of the HPMC shells at pH 6.8. Notably, the HPMC shells did not occlude the granulation as observed with the gelatin shells. The study demonstrated that the dissolution of capsule formulations in neutral pH media was significantly affected by the fill weight, sinker design, and capsule shell type. Careful selection of these parameters is essential to objectively evaluate the in vitro drug release.

BMS309403 stimulates glucose uptake in myotubes through activation of AMP-activated protein kinase.[Pubmed:22952994]

PLoS One. 2012;7(8):e44570.

BMS309403 is a biphenyl azole inhibitor against fatty acid binding protein 4 (FABP4) and regarded as a lead compound for effective treatment of obesity related cardio-metabolic diseases. Here we discovered an off-target activity of BMS309403 in that it stimulates glucose uptake in C2C12 myotubes in a temporal and dose dependent manner via activation of AMP-activated protein kinase (AMPK) signaling pathway but independent of FABPs. Further analysis indicated that BMS309403 activates AMPK through increasing the ratio of intracellular AMP:ATP while decreasing mitochondrial membrane potential. These findings provide mechanistic insights on the action of BMS309403.

Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2.[Pubmed:17554340]

Nature. 2007 Jun 21;447(7147):959-65.

Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.

Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP).[Pubmed:17502136]

Bioorg Med Chem Lett. 2007 Jun 15;17(12):3511-5.

Herein we report the first disclosure of biphenyl azoles that are nanomolar binders of adipocyte fatty acid binding protein (aFABP or aP2) with up to thousand-fold selectivity against muscle fatty acid binding protein and epidermal fatty acid binding protein. In addition a new radio-ligand to determine binding against the three fatty acid binding proteins was also synthesized.

BMS-309403 is a potent, selective and cell-permeable inhibitor of adipocyte fatty acid binding protein (FABP4) with a Ki of less than 2 nM, which exhibits Ki values of 250 nM for FABP3 and 350 nM for FABP5. BMS-309403 interacts with the fatty-acid-binding pocket within the interior of the protein and competitively inhibits the binding of endogenous fatty acids .

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