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.
Satoru Ito  1 ,  Yukari Hirata ,  Yasushi Nagatomi ,  Atsushi Satoh ,  Gentaroh Suzuki ,  Toshifumi Kimura ,  Akio Satow ,  Shunsuke Maehara ,  Hirohiko Hikichi ,  Mikiko Hata ,  Hisashi Ohta ,  Hiroshi Kawamoto
Affiliations
  • 1. Tsukuba Research Institute, Banyu Pharmaceutical CO., Ltd, 3 Okubo, Tsukuba 300-2611, Japan. [email protected]
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.