by Heike Schönherr, Tim Cernak*
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(sp2)-H and C(sp3)-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.
It′s a kind of magic: The methyl group is one of the
most prominent functional groups in bioactive small molecules and appears in
more than 67 % of the top-selling drugs. This Review highlights examples of the
magic methyl effect, whereby the installation of a single methyl group boosts
potency by more than two orders of magnitude. New C-H activation reactions are
required to facilitate the direct introduction of methyl groups.
Angewandte Chemie International Edition
Article first published online: 22 OCT 2013
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