Obesity is associated with a wide range of public health and economic problems throughout diverse demographic groups. As there is a high incidence of insulin resistance and type-2 diabetes among the obese, a mechanistic understanding of the relationship between insulin resistance and caloric consumption / obesity is needed. In cases of obesity and insulin resistance, triacylglycerides (TAG) accumulate within skeletal muscle cell; however, the mechanism of this relationship is not well understood. The research program described herein therefore sought small molecule probes that inhibit TAG accumulation. Toward this end, screening of 227,000 compounds resulted in the identification of MLS-0308942, which inhibited TAG accumulation with an IC50 of 1.7 μM. Subsequent medicinal chemistry follow up identified MLS-0472732 (ML377), which had similar potency (IC50 1.1 μM) with some improved ADME/T properties. Data were confirmed in the H9c2 high content assay (IC50 = 0.84 and 0.79 μM, respectively, with full response) and in a human primary cell assay. Furthermore, the compounds tested negatively for DGAT inhibition and cytotoxicity. Several additional analogs with comparable potency were observed, and the established SAR suggests the synthesis of new analogs in the future, which may address the poor microsomal stability exhibited thus far with the new series of compounds.