Methyl groups are very common in drug molecules. As reported by Heike Schonherr and Tim Cernak1, more than half of the top-selling drugs contains a CH3. A simple substitution of a C-H with a methyl can increase the potency of a compound by more than 100-fold.
The effect of C-H methylation primarily affects the conformation of the original molecule. Based on this reported statistical analysis2 the effect of methyl can be equally positive or negative. However a positive effect could be decisive in a drug discovery program.
Effect of ortho substitution3,4.
Effect of ring substitution5
Effect on rotatable bond6
Even if the methyl can be seen as a potential hot spot for metabolism. The addition of the methyl next to a metabolism position can improve metabolic stability.7
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- Heike Schonherr and Tim Cernak, Angew. Chem Int. Ed. 2013, 52, 12256-12267
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