Title:The Structure-property Relationships of Clinically Approved
Protease Inhibitors
Volume: 31
Issue: 12
关键词:
结构-性质关系、蛋白酶抑制剂、肽模拟物、先导化合物优化、候选药物选择、药物发现。
摘要:
Background: Proteases play important roles in the regulation of many physiological
processes, and protease inhibitors have become one of the important drug classes.
Especially because the development of protease inhibitors often starts from a substrate-
based peptidomimetic strategy, many of the initial lead compounds suffer from pharmacokinetic
liabilities.
Objective: To reduce drug attrition rates, drug metabolism and pharmacokinetics studies
are fully integrated into modern drug discovery research, and the structure-property relationship
illustrates how the modification of the chemical structure influences the pharmacokinetic
and toxicological properties of drug compounds. Understanding the structure-
property relationships of clinically approved protease inhibitor drugs and their analogues
could provide useful information on the lead-to-candidate optimization strategies.
Methods: About 70 inhibitors against human or pathogenic viral proteases have been approved
until the end of 2021. In this review, 17 inhibitors are chosen for the structure-
property relationship analysis because detailed pharmacological and/or physicochemical
data have been disclosed in the medicinal chemistry literature for these inhibitors
and their close analogues.
Results: The compiled data are analyzed primarily focusing on the pharmacokinetic or
toxicological deficiencies found in lead compounds and the structural modification strategies
used to generate candidate compounds.
Conclusion: The structure-property relationships hereby summarized how the overall
druglike properties could be successfully improved by modifying the structure of protease
inhibitors. These specific examples are expected to serve as useful references and
guidance for developing new protease inhibitor drugs in the future.
