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Structural simplification: an efficient strategy in lead optimization.

ABSTRACT: The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding "molecular obesity". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.

SUBMITTER: Wang S

PROVIDER: S-EPMC6804494 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Structural simplification: an efficient strategy in lead optimization.

Wang Shengzheng S Dong Guoqiang G Sheng Chunquan C

Acta pharmaceutica Sinica. B 20190606 5

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding "molecular obesity". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their phar ...[more]

PMID: 31649841

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