Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 approximately 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented.
Li S, Xu H, Cui S, Wu F, Zhang Y, Su M, Gong Y, Qiu S, Jiao Q, Qin C, Shan J, Zhang M, Wang J, Yin Q, Xu M, Liu X, Wang R, Zhu L, Li J, Xu Y, Jiang H, Zhao Z, Li H (2016) Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes Journal of Medicinal Chemistry59: 6772-90
Li S, Xu H, Cui S, Wu F, Zhang Y, Su M, Gong Y, Qiu S, Jiao Q, Qin C, Shan J, Zhang M, Wang J, Yin Q, Xu M, Liu X, Wang R, Zhu L, Li J, Xu Y, Jiang H, Zhao Z, Li H (2016) Journal of Medicinal Chemistry59: 6772-90
