2. Academic Validation
  3. Long Residence Time at the Vasopressin V2 Receptor Translates into Superior Inhibitory Effects in Ex Vivo and In Vivo Models of Autosomal Dominant Polycystic Kidney Disease

Long Residence Time at the Vasopressin V2 Receptor Translates into Superior Inhibitory Effects in Ex Vivo and In Vivo Models of Autosomal Dominant Polycystic Kidney Disease

  • J Med Chem. 2022 Jun 9;65(11):7717-7728. doi: 10.1021/acs.jmedchem.2c00011.
Haoran Zhang 1,  Wenzhong Yan 2,  Yongzhan Sun 3,  Haoxing Yuan 1,  Limin Su 1,  Xudong Cao 1,  Peng Wang 1,  Zhou Xu 1,  Youhui Hu 1,  Zhongjian Wang 1,  Yinan Wang 1,  Kequan Fu 1,  Ying Sun 1,  Yupeng Chen 3,  Jianjun Cheng 2,  Dong Guo 1
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, China.
  • 2 iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • 3 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Institute of Urology, Tianjin Medical University, Tianjin 300070, China.
PMID: 35363466 DOI: 10.1021/acs.jmedchem.2c00011
Abstract

Prevailing strategies directing early-phase drug discovery heavily rely on equilibrium-based metrics such as affinity, which overlooks the kinetic process of a drug molecule interacting with its target. Herein, we developed a number of vasopressin V2 receptor (V2R) antagonists with divergent binding affinities and kinetics for autosomal dominant polycystic kidney disease (ADPKD). Surprisingly, the residence time of the V2R antagonists, but not their affinity, was correlated with the efficacy in both ex vivo and in vivo models of ADPKD. We envision that the kinetics-directed drug candidate selection and development may have general applicability for ADPKD and other therapeutic areas as well.

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