文章基本信息

标题：Distribution- and Metabolism-Based Drug Discovery: A Potassium-Competitive Acid Blocker as a Proof of Concept
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作者：Ming-Shu Wang ; Yi Gong ; Lin-Sheng Zhuo 等
期刊名称：Research
电子版ISSN：2639-5274
出版年度：2022
卷号：2022
页码：1-12
DOI：10.34133/2022/9852518
语种：English
出版社：American Association for the Advancement of Science
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.