title: Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.
abstract: Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Izzat T
authors.initials: IT
authors.lastname: Raheem
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Schreier
authors.affiliation: Basic Pharmaceutical Sciences, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Joy
authors.initials: J
authors.lastname: Fuerst
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Liza
authors.initials: L
authors.lastname: Gantert
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hostetler
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Huszar
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Aniket
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Monika
authors.initials: M
authors.lastname: Kandebo
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Somang H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Discovery Process Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Bennett
authors.initials: B
authors.lastname: Ma
authors.affiliation: Chemistry Modeling and Informatics, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Georgia
authors.initials: G
authors.lastname: McGaughey
authors.affiliation: Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Shipe
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Uslaner
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: George H
authors.initials: GH
authors.lastname: Vandeveer
authors.affiliation: Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Smith
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008253:Macaca mulatta; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000188:drug therapy* / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D010726:Phosphodiesterase Inhibitors; C000609292:PyP-1 compound; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: Antipsychotic activity; Cognitive improvement; Fragment-based drug discovery; Phosphodiesterase 10A; Positron emission tomography; Pyrazolopyrimidine; Rational design; Schizophrenia