Design of Potent and Druglike Nonphenolic Inhibitors for Catechol O-Methyltransferase Derived from a Fragment Screening Approach Targeting the S-Adenosyl-l-methionine Pocket

J Med Chem. 2016 Nov 23;59(22):10163-10175. doi: 10.1021/acs.jmedchem.6b00927. Epub 2016 Oct 14.


A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed the identification of structurally related fragments of high ligand efficiency and with activity on the described orthogonal assays. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported. These compounds represent a novel series of potent COMT inhibitors that might be further optimized to new drugs useful for the treatment of Parkinson's disease, as adjuncts in levodopa based therapy, or for the treatment of schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catechol O-Methyltransferase / metabolism*
  • Catechol O-Methyltransferase Inhibitors / chemical synthesis
  • Catechol O-Methyltransferase Inhibitors / chemistry
  • Catechol O-Methyltransferase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Humans
  • Models, Molecular
  • Molecular Structure
  • S-Adenosylmethionine / chemical synthesis
  • S-Adenosylmethionine / chemistry
  • S-Adenosylmethionine / pharmacology*
  • Structure-Activity Relationship


  • Catechol O-Methyltransferase Inhibitors
  • S-Adenosylmethionine
  • Catechol O-Methyltransferase