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

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• 作者：Shiliang Li ; Hongling Xu ; Shichao Cui ; Fangshu Wu ; Youli Zhang ; Mingbo Su ; Yinghui Gong ; Shaobing Qiu ; Qian Jiao ; Chun Qin ; Jiwei Shan ; Ming Zhang ; Jiawei Wang ; Qiao Yin ; Minghao Xu ; Xiaofeng Liu ; Rui Wang ; Lili Zhu ; Jia Li ; Yufang Xu ; Hualiang Jiang ; Zhenjiang Zhao ; Jingya Li ; Honglin Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 28, 2016
• 年：2016
• 卷：59
• 期：14
• 页码：6772-6790
• 全文大小：937K
• 年卷期：0
• ISSN：1520-4804

文摘

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 ≈ 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.