c-Jun NH2 terminal kinase (JNK) plays an important role in insulin resistance, however identification of pharmacologically potent and selective small-molecule JNK inhibitors has been limited. Compound A has a cell IC₅₀ of 102nM and is at least 100-fold selective against related kinases and 27-fold selective against GSK-3 and CDK-2. In C57BL/6 mice Compound A reduced LPS-mediated increases in both plasma cytokine levels and phosphorylated c-Jun in adipose. Treatment of mice fed a high-fat diet with compound A for 3 weeks resulted in a 13.1±1% decrease in body-weight and a 9.3±1.5% decrease in %fat, compared to a 6.6±2.1% increase in body-weight and increase in %fat of 6.7 ±2.1% in vehicle treated mice. Mice pair-fed to those that received compound A, exhibited a body-weight decrease of 7±1% and a decrease in % fat of 1.6±1.3% suggesting that reductions in food intake could not account solely for the reductions in adiposity observed. Compound A dosed at 30mg/Kg for 13 days in high-fat fed mice resulted in significant decrease in phosphorylated c-jun in adipose accompanied by a decrease in weight and reductions in glucose and triglycerides and increases in insulin sensitivity to levels comparable to that in lean control mice. The ability of compound A to reduce the insulin-stimulated phosphorylation of IRS-1 on Ser 307 and partially reverse the FFA-inhibition of glucose uptake in 3T3L1 adipocytes suggests that enhancement of insulin signaling in addition to weight loss may contribute to the effects of compound A on insulin sensitization in vivo. Pharmacological inhibition of JNK using compound A may therefore offer an effective therapy for type 2 diabetes mediated at least in-part via weight reduction.