4xue

Publication Abstract from PubMed

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.

Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT).,Harrison ST, Poslusney MS, Mulhearn JJ, Zhao Z, Kett NR, Schubert JW, Melamed JY, Allison TJ, Patel SB, Sanders JM, Sharma S, Smith RF, Hall DL, Robinson RG, Sachs NA, Hutson PH, Wolkenberg SE, Barrow JC ACS Med Chem Lett. 2015 Jan 26;6(3):318-23. doi: 10.1021/ml500502d. eCollection, 2015 Mar 12. PMID:25815153^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.