title: Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT).
abstract: 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.
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Scott T
authors: ST
authors: Harrison
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Michael S
authors: MS
authors: Poslusney
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: James J
authors: JJ
authors: Mulhearn
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Zhijian
authors: Z
authors: Zhao
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Nathan R
authors: NR
authors: Kett
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Jeffrey W
authors: JW
authors: Schubert
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Jeffrey Y
authors: JY
authors: Melamed
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Timothy J
authors: TJ
authors: Allison
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Sangita B
authors: SB
authors: Patel
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: John M
authors: JM
authors: Sanders
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Sujata
authors: S
authors: Sharma
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Robert F
authors: RF
authors: Smith
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Dawn L
authors: DL
authors: Hall
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Ronald G
authors: RG
authors: Robinson
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Nancy A
authors: NA
authors: Sachs
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Pete H
authors: PH
authors: Hutson
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: Scott E
authors: SE
authors: Wolkenberg
authors: Department of Medicinal Chemistry, Global Structural Biology, Chemical Modeling and Informatics, and Department of Neuroscience Research, Merck Research Laboratories , Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors: James C
authors: JC
authors: Barrow
keywords: Catechol O-methyl transferase; catechol mimic; cognition; schizophrenia