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Review
. 2013 Nov 18;52(47):12256-67.
doi: 10.1002/anie.201303207. Epub 2013 Oct 22.

Profound methyl effects in drug discovery and a call for new C-H methylation reactions

Heike Schönherr  1 , Tim Cernak
Affiliations
Review

Profound methyl effects in drug discovery and a call for new C-H methylation reactions

Heike Schönherr et al. Angew Chem Int Ed Engl. .

Abstract

The methyl group is one of the most commonly occurring carbon fragments in small-molecule drugs. This simplest alkyl fragment appears in more than 67 % of the top-selling drugs of 2011 and can modulate both the biological and physical properties of a molecule. This Review focuses on so-called magic methyl effects on binding potency, where the seemingly mundane change of CH to CMe improves the IC50 value of a drug candidate more than 100-fold. This discussion is followed by a survey of recent advances in synthetic chemistry that allow the direct methylation of C(sp(2) )H and C(sp(3) )H bonds. It is our hope that the relevance of the meager methyl group to drug discovery as presented herein will inspire reports on new CH methylation reactions.

Keywords: CH activation; alkylation; conformations; drug discovery; methyl groups.

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