Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: a potential treatment for psychotic disorders.
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.
Ito
Satoru
S
Tsukuba Research Institute, Banyu Pharmaceutical CO., Ltd, 3 Okubo, Tsukuba 300-2611, Japan. satoru_ito@merck.com
Hirata
Yukari
Y
Nagatomi
Yasushi
Y
Satoh
Atsushi
A
Suzuki
Gentaroh
G
Kimura
Toshifumi
T
Satow
Akio
A
Maehara
Shunsuke
S
Hikichi
Hirohiko
H
Hata
Mikiko
M
Ohta
Hisashi
H
Kawamoto
Hiroshi
H
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
D014150:Antipsychotic Agents; D007211:Indoles; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1