title: Synthesis and optimization of N-heterocyclic pyridinones as catechol-O-methyltransferase (COMT) inhibitors.
abstract: A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition.
authors.affiliation: Medicinal Chemistry, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Medicinal Chemistry, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Harrison
authors.affiliation: Medicinal Chemistry, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Schubert
authors.affiliation: Chemistry, Modeling, and Informatics, Merck & Co., Inc., West Point, PA, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.affiliation: Pharmacokinetics, Pharmacodynamics, & Drug Metabolism, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Stacey
authors.initials: S
authors.lastname: Polsky-Fisher
authors.affiliation: Pharmacokinetics, Pharmacodynamics, & Drug Metabolism, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Nanyan Rena
authors.initials: NR
authors.lastname: Zhang
authors.affiliation: Pharmacokinetics, Pharmacodynamics, & Drug Metabolism, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Debra
authors.initials: D
authors.lastname: McLoughlin
authors.affiliation: Pharmacokinetics, Pharmacodynamics, & Drug Metabolism, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gibson
authors.affiliation: Neuroscience Research, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Robinson
authors.affiliation: Neuroscience Research, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Sachs
authors.affiliation: Neuroscience Research, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Monika
authors.initials: M
authors.lastname: Kandebo
authors.affiliation: Neuroscience Research, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Lihang
authors.initials: L
authors.lastname: Yao
authors.affiliation: Neuroscience Research, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Smith
authors.affiliation: Neuroscience Research, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Pete H
authors.initials: PH
authors.lastname: Hutson
authors.affiliation: Medicinal Chemistry, Merck & Co., Inc., West Point, PA, United States.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Wolkenberg
authors.affiliation: Medicinal Chemistry, Merck & Co., Inc., West Point, PA, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
mesh_terms: D000818:Animals; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D006571:Heterocyclic Compounds; D011728:Pyridones; D002394:Catechol O-Methyltransferase
keywords: Catechol O-methyl transferase; Cognition; Schizophrenia