2. Academic Validation
  3. 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

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

  • J Med Chem. 2016 Jul 28;59(14):6772-90. doi: 10.1021/acs.jmedchem.6b00505.
Shiliang Li 1,  Hongling Xu 1,  Shichao Cui 2,  Fangshu Wu 1,  Youli Zhang 1,  Mingbo Su 2,  Yinghui Gong 1,  Shaobing Qiu 1,  Qian Jiao 1,  Chun Qin 1,  Jiwei Shan 1,  Ming Zhang 1,  Jiawei Wang 1,  Qiao Yin 1,  Minghao Xu 1,  Xiaofeng Liu 1,  Rui Wang 1,  Lili Zhu 1,  Jia Li 2,  Yufang Xu 1,  Hualiang Jiang 2,  Zhenjiang Zhao 1,  Jingya Li 2,  Honglin Li 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Shanghai 201203, China.
PMID: 27396490 DOI: 10.1021/acs.jmedchem.6b00505
Abstract

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.

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