biostudies-literature00510Unknown6(3)Harrison ST3-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 Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.ACS medicinal chemistry letters318-23https://www.ebi.ac.uk/biostudies/studies/S-EPMC4360154biostudies-literatureSynthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT).PMC4360154Harrison STPoslusney MSMulhearn JJSanders JMSharma SHall DLPatel SBHutson PHBarrow JCZhao ZRobinson RGKett NRSachs NASchubert JWAllison TJWolkenberg SESmith RFMelamed JY51falseSynthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT).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 Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.2015-01-01T00:00:00Z2015 Mar2024-11-21T02:44:46.655Z2019-03-27T01:48:12ZS-EPMC43601542581515310.1021/ml500502d