Design, Optimization, and Biological Evaluation of First-in-Class Triple Inhibitors of SGLT1, SGLT2, and DPP4 for Type 2 Diabetes Mellitus

Type 2 diabetes care has evolved with DPP4, SGLT2, and SGLT1/2 inhibitors, but still many patients face hyperglycemia and high cardiorenal risk. Here, we designed unprecedented triple-targeted inhibitors of SGLT1/2 and DPP4 by leveraging information on binding modes of existing inhibitors. Balanced inhibition was achieved across targets while maintaining desirable pharmacokinetics with long-lasting kidney exposure. Lead compounds 64 (IC₅₀: DPP4 = 356 nM, SGLT1 = 1.29 μM, SGLT2 = 170 nM), 99 (58 nM, 23 nM, 0.8 nM), and 101 (72 nM, 6.7 nM, 0.8 nM) induced glucosuria in nondiabetic rats. Following oral glucose challenge in Zucker diabetic rats, they demonstrated statistically superior plasma glycemic control versus SGLT2-selective inhibitor dapagliflozin and conferred a prolonged increase in active GLP-1 relative to the SGLT1/2 inhibitor sotagliflozin, implying synergistic SGLT1 and DPP4 inhibition. These results support triple-targeted inhibitors as multitarget, multiorgan drug candidates for improved glycemic control and cardiorenal benefits.