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 <b>64</b> (IC₅₀: DPP4 = 356 nM, SGLT1 = 1.29 μM, SGLT2 = 170 nM), <b>99</b> (58 nM, 23 nM, 0.8 nM), and <b>101</b> (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.