Development of a succinyl CoA:3-ketoacid CoA transferase inhibitor selective for peripheral tissues that improves glycemia in obesity
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. <i>In silico</i> 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.
Authors
- Megan E. Capozzi (ORCID: https://orcid.org/0000-0002-7587-0663)
- John R. Ussher (ORCID: https://orcid.org/0000-0001-9574-5707)
- Michael Overduin (ORCID: https://orcid.org/0000-0002-3114-6585)
- Kunyan Yang
- Carlos A. Velázquez‐Martínez (ORCID: https://orcid.org/0000-0003-4535-1835)
- Christina T. Saed (ORCID: https://orcid.org/0000-0002-4469-330X)
- Rabih Abou Farraj (ORCID: https://orcid.org/0000-0002-1627-8467)
- Rakesh Bhat (ORCID: https://orcid.org/0000-0001-7649-0470)
- Cory S. Wagg
- Jenilee Woodfield (ORCID: https://orcid.org/0009-0005-0665-4587)
- Farah Eaton (ORCID: https://orcid.org/0000-0002-8251-8908)
- J. N. Mark Glover
- Dion R. Brocks (ORCID: https://orcid.org/0000-0001-5024-2268)
- Melinda Wuest (ORCID: https://orcid.org/0000-0003-0735-2749)
- Amanda A. Greenwell (ORCID: https://orcid.org/0000-0003-0355-2938)
- Jonathan E. Campbell (ORCID: https://orcid.org/0000-0001-8223-1600)
- Jordan S. F. Chan (ORCID: https://orcid.org/0009-0006-1567-8772)
- Frank Wuest (ORCID: https://orcid.org/0000-0002-6705-6450)
- Indiresh A Mangra-Bala (ORCID: https://orcid.org/0009-0007-2259-1664)
- Seyed Amirhossein Tabatabaei Dakhili
- Keshav Gopal (ORCID: https://orcid.org/0000-0002-3320-2990)
- Tanin Shafaati
- Sally R. Ferrari
- Hamdah Al Nebaihi
Institutions
- University of Alberta (CA)
- Duke University (US)
Publication Details
- Journal
- iScience
- Published
- 2025-04-04
- DOI
- https://doi.org/10.1016/j.isci.2025.112336
- Citations
- 2
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 2.33
Funders
- Canadian Institutes of Health Research