title: Discovery of orally active pyrazoloquinolines as potent PDE10 inhibitors for the management of schizophrenia.
abstract: A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high affinity. From the SAR study and our lead optimization efforts, compounds 16 and 27 were found to possess potent oral antipsychotic activity in the MK-801 induced hyperactive rat model.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. shu-wei.yang@merck.com
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Yang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Smotryski
authors.forename: William T
authors.initials: WT
authors.lastname: McElroy
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tan
authors.forename: Ginny
authors.initials: G
authors.lastname: Ho
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Mario
authors.initials: M
authors.lastname: Guzzi
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Deborra
authors.initials: D
authors.lastname: Mullins
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.forename: Alan
authors.initials: A
authors.lastname: Hruza
authors.forename: Tze-Ming
authors.initials: TM
authors.lastname: Chan
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.forename: Carina
authors.initials: C
authors.lastname: Bleickardt
authors.forename: Robert
authors.initials: R
authors.lastname: Hodgson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D008968:Molecular Conformation; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D016291:Dizocilpine Maleate; C119843:PDE10A protein, human; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases