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Volume 11, 2020
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Scaffold-hopping as a strategy to address metabolic liabilities of aromatic compounds

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Abstract

Understanding and minimizing oxidative metabolism of aromatic compounds is a key hurdle in lead optimization. Metabolic processes not only clear compounds from the body, but they can also transform parent compounds into reactive metabolites. One particularly useful strategy when addressing metabolically labile or oxidation-prone structures is scaffold-hopping. Replacement of an aromatic system with a more electron-deficient ring system can often increase robustness towards cytochrome P450-mediated oxidation while conserving the structural requirements of the pharmacophore. The most common example of this substitution strategy, replacement of a phenyl ring with a pyridyl substituent, is prevalent throughout the literature; however scaffold-hopping encompasses a much wider scope of heterocycle replacement. This review will showcase recent examples where different scaffold-hopping approaches were used to reduce metabolic clearance or block the formation of reactive metabolites. Additionally, we will highlight considerations that should be made to garner the most benefit from a scaffold-hopping strategy for lead optimization.

Graphical abstract: Scaffold-hopping as a strategy to address metabolic liabilities of aromatic compounds

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Article information


Submitted
10 Aug 2019
Accepted
09 Oct 2019
First published
16 Dec 2019

RSC Med. Chem., 2020,11, 18-29
Article type
Review Article

Scaffold-hopping as a strategy to address metabolic liabilities of aromatic compounds

P. R. Lazzara and T. W. Moore, RSC Med. Chem., 2020, 11, 18
DOI: 10.1039/C9MD00396G

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