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

作者：Haoran Zhang, Wenzhong Yan, Yongzhan Sun, Haoxing Yuan, Limin Su, Xudong Cao, Peng Wang, Zhou Xu, Youhui Hu, Zhongjian Wang, Yinan Wang, Kequan Fu, Ying Sun, Yupeng Chen, Jianjun Cheng, Dong Guo · 发表于：Journal of Medicinal Chemistry · 年份：2022 · DOI：10.1021/acs.jmedchem.2c00011 · 被引用次数：29 · 研究领域：Genetic and Kidney Cyst Diseases、Renal and related cancers、Pancreatic function and diabetes

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 V 2 receptor (V 2 R) antagonists with divergent binding affinities and kinetics for autosomal dominant polycystic kidney disease (ADPKD). Surprisingly, the residence time of the V 2 R 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.