title: Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.
abstract: Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Shipe
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Sharik
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Cory R
authors.initials: CR
authors.lastname: Theberge
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Smith
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry; D017208:Rats, Wistar; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D016291:Dizocilpine Maleate; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases