title: Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: a potential treatment for psychotic disorders.
abstract: We describe here the discovery and biological profile of a series of isoindolinone derivatives as developed mGluR1 antagonists. Our combined strategy of rapid parallel synthesis and conventional medicinal optimization successfully led to N-cyclopropyl 22 and N-isopropyl isoindolinone analogs 21 and 23 with improved in vivo DMPK profiles. Moreover the most advanced analog 23 showed an oral antipsychotic-like effect at a dose of 1mg/kg in an animal model.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical CO., Ltd, 3 Okubo, Tsukuba 300-2611, Japan. satoru_ito@merck.com
authors.forename: Satoru
authors.initials: S
authors.lastname: Ito
authors.forename: Yukari
authors.initials: Y
authors.lastname: Hirata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nagatomi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Satoh
authors.forename: Gentaroh
authors.initials: G
authors.lastname: Suzuki
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Kimura
authors.forename: Akio
authors.initials: A
authors.lastname: Satow
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Maehara
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Hikichi
authors.forename: Mikiko
authors.initials: M
authors.lastname: Hata
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D011618:Psychotic Disorders / Q000188:drug therapy*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D007211:Indoles; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1