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.