title: Profound methyl effects in drug discovery and a call for new C-H methylation reactions.
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.
authors.affiliation: Department of Ophthalmology, Columbia University Medical Center, 635 W 165th St., New York, NY, 10032 (USA).
authors.forename: Heike
authors.initials: H
authors.lastname: Schönherr
authors.forename: Tim
authors.initials: T
authors.lastname: Cernak
mesh_terms: D002244:Carbon / Q000737:chemistry; D055808:Drug Discovery; D006859:Hydrogen / Q000737:chemistry; D006860:Hydrogen Bonding; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D011789:Quantum Theory; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism
chemical_list: D054852:Small Molecule Libraries; D002244:Carbon; D006859:Hydrogen; D008780:Methyltransferases
keywords: CH activation; alkylation; conformations; drug discovery; methyl groups