Poslusney M.S.,Lieber Institute for Brain Development |
Allison T.J.,Global Structural Biology |
Patel S.B.,Global Structural Biology |
Sanders J.M.,Chemical Modeling and Informatics |
And 7 more authors.
ACS Medicinal Chemistry Letters | Year: 2015
3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg2+. The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors. © 2015 American Chemical Society.