Profound Methyl Effects in Drug Discovery and a Call for New C[BOND]H Methylation Reactions



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[BOND]H to C[BOND]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)[BOND]H and C(sp3)[BOND]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[BOND]H methylation reactions.