Tabatabaei Dakhili Seyed Amirhossein, Yang Kunyan, Al Nebaihi Hamdah, Greenwell Amanda A, Wuest Melinda, Woodfield Jenilee, Farraj Rabih Abou, Saed Christina T, Chan Jordan S F, Bhat Rakesh K, Mangra-Bala Indiresh A, Shafaati Tanin, Gopal Keshav, Eaton Farah, Ferrari Sally R, Wagg Cory S, Capozzi Megan E, Campbell Jonathan E, Overduin Michael, Velazquez-Martinez Carlos A, Glover J N Mark, Wuest Frank, Brocks Dion R, Ussher John R
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada.
iScience. 2025 Apr 3;28(5):112336. doi: 10.1016/j.isci.2025.112336. eCollection 2025 May 16.
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. 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.
许多2型糖尿病（T2D）患者因现有疗法的不良反应而无法使用。因此，需要针对独特机制的新型降糖药物。研究表明，由于肌肉特异性缺失琥珀酰辅酶A：3-酮酸辅酶A转移酶（SCOT）导致酮氧化减少，可保护小鼠免受肥胖相关的高血糖影响。研究发现抗精神病药物二苯基丁基哌啶可以抑制SCOT并减轻肥胖相关的高血糖。由于酮是大脑的主要燃料，而二苯基丁基哌啶有中枢神经系统相关的不良反应，我们旨在开发一种外周选择性SCOT抑制剂（PSSI）。利用源自二苯基丁基哌啶-SCOT相互作用的药效团，我们合成了PSSI-51，它在外周组织而非脑组织中抑制SCOT活性，同时减少心肌酮氧化。重要的是，与二苯基丁基哌啶匹莫齐特相比，PSSI-51治疗改善了肥胖小鼠的血糖水平，并显示出脑内蓄积减少。我们认为PSSI-51可为优化一类新型的脑渗透性差的SCOT抑制剂治疗T2D奠定基础。
