title: The SAR development of dihydroimidazoisoquinoline derivatives as phosphodiesterase 10A inhibitors for the treatment of schizophrenia.
abstract: The identification of potent and orally active dihydroimidazoisoquinolines as PDE 10A inhibitors is reported. The SAR development led to the discovery of compound 35 as a potent, selective, and orally active PDE10A inhibitor. Compound 35 inhibited MK-801-induced hyperactivity at 3mg/kg and displayed a 10-fold separation between the minimal effective doses for inhibition of MK-801-induced hyperactivity and hypolocomotion in rats.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States. ginny.ho@merck.com
authors.forename: Ginny D
authors.initials: GD
authors.lastname: Ho
authors.forename: W
authors.initials: W
authors.lastname: Michael Seganish
authors.forename: Ana
authors.initials: A
authors.lastname: Bercovici
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Rachel
authors.initials: R
authors.lastname: Van Rijn
authors.forename: Alan
authors.initials: A
authors.lastname: Hruza
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.forename: Deborra
authors.initials: D
authors.lastname: Mullins
authors.forename: Mario
authors.initials: M
authors.lastname: Guzzi
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Carina
authors.initials: C
authors.lastname: Bleickardt
authors.forename: Robert
authors.initials: R
authors.lastname: Hodgson
mesh_terms: D000818:Animals; D019540:Area Under Curve; D018360:Crystallography, X-Ray; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry / Q000378:metabolism; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000737:chemistry / Q000378:metabolism; D016291:Dizocilpine Maleate; D000882:Haplorhini; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D007093:Imidazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D007546:Isoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D008297:Male; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D012559:Schizophrenia / Q000188:drug therapy / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D011619:Psychotropic Drugs; D016291:Dizocilpine Maleate; C512064:PDE10A protein, rat; D010727:Phosphoric Diester Hydrolases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517290:Pde3a protein, rat; C517461:Pde7a protein, rat