Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: a potential treatment for psychotic disorders

Satoru Ito; Yukari Hirata; Yasushi Nagatomi; Atsushi Satoh; Gentaroh Suzuki; Toshifumi Kimura; Akio Satow; Shunsuke Maehara; Hirohiko Hikichi; Mikiko Hata; Hisashi Ohta; Hiroshi Kawamoto

doi:10.1016/j.bmcl.2009.07.145

Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: a potential treatment for psychotic disorders

Bioorg Med Chem Lett. 2009 Sep 15;19(18):5310-3. doi: 10.1016/j.bmcl.2009.07.145. Epub 2009 Aug 3.

Authors

Satoru Ito¹, Yukari Hirata, Yasushi Nagatomi, Atsushi Satoh, Gentaroh Suzuki, Toshifumi Kimura, Akio Satow, Shunsuke Maehara, Hirohiko Hikichi, Mikiko Hata, Hisashi Ohta, Hiroshi Kawamoto

Affiliation

¹ Tsukuba Research Institute, Banyu Pharmaceutical CO., Ltd, 3 Okubo, Tsukuba 300-2611, Japan. satoru_ito@merck.com

PMID: 19692242
DOI: 10.1016/j.bmcl.2009.07.145

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.

MeSH terms

Animals
Antipsychotic Agents / chemistry
Antipsychotic Agents / pharmacology*
Antipsychotic Agents / therapeutic use
Hepatocytes / drug effects
Humans
Indoles / chemistry
Indoles / pharmacology*
Indoles / therapeutic use
Mice
Psychotic Disorders / drug therapy*
Rats
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Receptors, Metabotropic Glutamate / metabolism*
Structure-Activity Relationship

Substances

Antipsychotic Agents
Indoles
Receptors, Metabotropic Glutamate
metabotropic glutamate receptor type 1