Magic methyl in medicinal chemistry

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.

ortho_methylation1

ortho_methylation2

Effect of ring substitution5

ring_methylation

Effect on rotatable bond6

bond_methylation

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

Methyl_stability

 

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  1. Heike Schonherr and Tim Cernak, Angew. Chem Int. Ed. 2013, 52, 12256-12267
  2. C. S. Leung, S. S. F. Leung, J. Tirado-Rives, W. L. Jorgensen, J. Med. Chem. 2012, 55, 4489 – 4500.
  3. F. Berardi, C. Abate, S. Ferorelli, A. F. de Robertis, M. Leopoldo, N.A. Colabufo, M. Niso, R. Perrone, J. Med. Chem. 2008, 51, 7523 – 7531.
  4. J. Y. Hwang, D. Smithson, F. Zhu, G. Holbrook,M. C. Connelly, M. Kaiser, R. Brun, R. K. Guy, J. Med. Chem. 2013, 56, 2850 – 2860.
  5. P. J. Coleman and coll. , Chem- MedChem 2012, 7, 415 – 424.
  6. G. F. Costello, R. James, J. S. Shaw, A.M. Slater, N. C. J. Stutchbury, J. Med. Chem. 1991, 34, 181 – 189.
  7. R.W. Friesen and coll., Bioorg. Med. Chem. Lett. 1998, 8, 2777 – 2782.

 

 

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