Diabetes is a fast growing worldwide chronic metabolic disorder. DPP-4 has been proved one of the most effective targets for T2DM treatment by the commercial success of Sitagliptin. Previously, iso-daphnetin, a natural product, was identified to show moderate bioactivity against DPP-4 (IC50 = 14.13 μM) through a reverse-docking based computational chemical biology approach. In this study, starting from this natural produce, scaffold hopping and pharmacophore grafting were deliberately conducted by using an efficient in house 3D molecular similarity calculation program SHAFTS. Then, the electrostatic complementary between the ligand and the receptor was attentively evaluated. Collectively, those ingenious drug design strategies bring us a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors with approximate 7400-fold boost in potency. The representative compound shows IC50 value around 2.0 nM with good selectivity and excellent pharmacokinetic profiles (F = 89 %). In the in vivo efficacy study, this compound displays sustained pharmacodynamic effect with a 3 mg/kg oral dose giving > 80% inhibition of DPP-4 activity within 24 h in ob/ob mice, which is comparable to the performance of the long-acting control Omarigliptin (MK-3102). Moreover, the efficacy of this inhibitor in improving the glucose tolerance is also comparative with Omarigliptin, suggesting itself a promising candidate as long-acting antidiabetic agent targeting DPP-4.

J. Med. Chem., 2016, 59 (14), 6772–6790