Background: Type 2 diabetes (T2D) is a swiftly growing disease which affects human
health seriously around the world. So far, nine DPP-4 inhibitors have been launched on the markets
for patients with T2D. The aminomethyl biaryl derivatives, with a novel structure scaffold, have been
proved as potential DPP-4 inhibitors. Our team focused on the modification of aminomethyl biaryl derivatives
through the pharmacophore model.
Method: A series of aminomethyl biaryl derivatives, which were designed according to the pharmacophore
model, were synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the
treatment of type 2 diabetes.
Results: A novel series of DPP-4 inhibitors with biaryl scaffold designed by pharmacophore model,
has been synthesized and identified. The IC50 level of compound A7, A25 and A26 in potency was
comparable to Sitagliptin. A25 showed more than 100-fold selectivity over DPP-7 and DPP-8.
Conclusion: The substitution 1,2,4-triazolyl group was proved to be a key discovery in increasing the
potency of this structural class of inhibitors.