Design, Synthesis, Structure–Activity Relationships, and Docking Studies of 1-(γ-1,2,3-Triazol Substituted Prolyl)-(S)-3,3-Difluoropyrrolidines as a Novel Series of Potent and Selective Dipeptidyl Peptidase-4 Inhibitors

Authors

  • Lei Zhang,

    1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, China
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  • Mingbo Su,

    1. National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai, China
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  • Jingya Li,

    1. National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai, China
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  • Xun Ji,

    1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, China
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  • Jiang Wang,

    1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, China
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  • Zeng Li,

    1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, China
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  • Jia Li,

    Corresponding author
    1. National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Shanghai, China
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  • Hong Liu

    Corresponding author
    1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, China
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Corresponding authors: Jia Li and Hong Liu, jli@mail.shcnc.ac.cn ; hliu@mail.shcnc.ac.cn

Abstract

Dipeptidyl peptidase-4 inhibitors hold great potential for the treatment of type 2 diabetes. A series of 1-(γ-1,2,3-triazol substituted prolyl)-(S)-3,3-difluoropyrrolidines were designed, synthesized, and evaluated as novel dipeptidyl peptidase-4 inhibitors. Most of the compounds exhibited good in vitro potency against dipeptidyl peptidase-4. Among these, compounds 7j, 7q, and 7s displayed good dipeptidyl peptidase-4 activity and excellent selectivity versus other proteases including dipeptidyl peptidase-8, dipeptidyl peptidase-9, and FAP. The possible binding modes of compounds 7j, 7q, and 7s with dipeptidyl peptidase-4 were also explored by molecular docking simulation.

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