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Design and Synthesis of (R)-1-Arylsulfonylpiperidine-2-carboxamides as 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Authors

  • Dr. Guangxin Xia,

    1. Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
    2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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    • These authors contributed equally to this work.

  • Lin Liu,

    1. Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
    2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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    • These authors contributed equally to this work.

  • Dr. Haiyan Liu,

    1. Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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  • Dr. Jianxin Yu,

    1. Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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  • Zhenmin Xu,

    1. Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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  • Qian Chen,

    1. Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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  • Chen Ma,

    1. Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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  • Dr. Ping Li,

    1. Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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  • Prof. Bing Xiong,

    Corresponding author
    1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
    • State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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  • Dr. Xuejun Liu,

    1. Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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  • Prof. Jingkang Shen

    Corresponding author
    1. Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
    2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
    • Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203 (China)
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Abstract

original image

R adamantly beats S: 11β-HSD1 is a target for treating metabolic syndrome. The R isomer 5 was selected as a starting point for optimization and SAR studies. Inhibitor 8 w emerged after several rounds of optimization, showing cross-species inhibition of human and mouse 11β-HSD1. It also displays a good DMPK profile in vitro, and was advanced to PK/PD evaluations in vivo. The results confirmed its dose-dependent activity in mice.

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