Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin

•We identified several highly potent DPP-4 inhibitors by hybrid compound design.•The most promising compound 2h was more potent than linagliptin and alogliptin.•Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9.•Compound 2h displayed significant glucose-lowering effect and good safety profile.•Compound 2h exhibited a potential as drug candidate for treating type 2 diabetes.

Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. The most promising compound 2h (IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that of alogliptin (IC50 = 2.63 nM) and linagliptin (IC50 = 0.77 nM), respectively. Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus was selected for further biological evaluation, including oral glucose tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute toxicity and hERG inhibition. The assay results showed that 2h displayed significant in vivo glucose-lowering effect and low risk of toxicity. Further studies are expected to confirm 2h as a potential drug candidate for the treatment of type 2 diabetes.

Graphical abstractA highly potent DPP-4 inhibitor 2h (IC50 = 0.31 nM) has been identified by hybrid compound design on the basis of SAR analysis and binding modes of linagliptin and alogliptin.Figure optionsDownload full-size imageDownload as PowerPoint slide