Distribution- and Metabolism-Based Drug Discovery: A Potassium-Competitive Acid Blocker as a Proof of Concept  

作　　者：Ming-Shu Wang Yi Gong Lin-Sheng Zhuo Xing-Xing Shi Yan-Guang Tian Chang-Kang Huang Wei Huang Guang-Fu Yang 

机构地区：[1]Key Laboratory of Pesticide e Chemical Biology of Ministry of Education,International Joint Research Center for Intelligent Biosensor Technology and Health,College of Chemistry,Central China Normal University,Wuhan 430079,China [2]Nanjing Shuohui Pharmatechnology Co.,Ltd.,Nanjing 210046,China

出　　处：《Research》2022年第4期609-620,共12页研究（英文）

基　　金：This work was supported by the National Key Research and Development Program of China(No.2017YFA0505200);the Key Research and Development Program of Hubei Province,China(2020BCB042);the Science and Technology ProgramofWuhan(No.2019020701011460).

摘　　要：Conventional methods of drug design require compromise in the form of side effects to achieve sufficient efficacy because targeting drugs to specific organs remains challenging.Thus,new strategies to design organ-specific drugs that induce little toxicity are needed.Based on characteristic tissue niche-mediated drug distribution(TNMDD)and patterns of drug metabolism into specific intermediates,we propose a strategy of distribution-and metabolism-based drug design(DMBDD);through a physicochemical property-driven distribution optimization cooperated with a well-designed metabolism pathway,SH-337,a candidate potassium-competitive acid blocker(P-CAB),was designed.SH-337 showed specific distribution in the stomach in the long term and was rapidly cleared from the systemic compartment.Therefore,SH-337 exerted a comparable pharmacological effect but a 3.3-fold higher no observed adverse effect level(NOAEL)compared with FDA-approved vonoprazan.This study contributes a proof-of-concept demonstration of DMBDD and provides a new perspective for the development of highly efficient,organ-specific drugs with low toxicity.

关 键 词：DRUGS ORGANS POTASSIUM 

分 类 号：R96[医药卫生—药理学]