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Updated: Sep 19, 2025

Study of In Vivo Glucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test OGTT and Insulin Tolerance Test ITT
Published on: January 7, 2018
Development of a succinyl CoA:3-ketoacid CoA transferase inhibitor selective for peripheral tissues that improves
Seyed Amirhossein Tabatabaei Dakhili1,2, Kunyan Yang1,2, Hamdah Al Nebaihi1
1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Abstract:
Many individuals with type 2 diabetes (T2D) cannot take current therapies due to their adverse effects. Thus, new glucose-lowering agents targeting unique mechanisms are needed. Studies have demonstrated that decreasing ketone oxidation, secondary to muscle-specific deletion of succinyl-CoA:3-ketoacid-CoA transferase (SCOT), protects mice against obesity-related hyperglycemia. In silico studies identified that the antipsychotic diphenylbutylpiperidines can inhibit SCOT and alleviate obesity-related hyperglycemia. Because ketones are a major brain fuel, whereas the diphenylbutylpiperidines have central nervous system-related adverse effects, we aimed to develop a peripheral selective SCOT inhibitor (PSSI). Using a pharmacophore derived from the diphenylbutylpiperidine-SCOT interaction, we synthesized PSSI-51, which inhibited SCOT activity in peripheral but not brain tissue, while decreasing myocardial ketone oxidation. Importantly, PSSI-51 treatment improved glycemia in obese mice and demonstrated reduced brain accumulation compared to the diphenylbutylpiperidine pimozide. We propose that PSSI-51 can lay the foundation for optimizing a new class of brain-impermeable SCOT inhibitors for treating T2D.
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