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...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 19; no. 18; pp. 5310 - 5313
Main Authors:	Ito, Satoru, Hirata, Yukari, Nagatomi, Yasushi, Satoh, Atsushi, Suzuki, Gentaroh, Kimura, Toshifumi, Satow, Akio, Maehara, Shunsuke, Hikichi, Hirohiko, Hata, Mikiko, Ohta, Hisashi, Kawamoto, Hiroshi
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 15-09-2009 Elsevier
Subjects:	Animals Antagonist Antipsychotic Agents - chemistry Antipsychotic Agents - pharmacology Antipsychotic Agents - therapeutic use Biological and medical sciences Glutamate Glutamatergic system (aspartate and other excitatory aminoacids) Hepatocytes - drug effects Humans Indoles - chemistry Indoles - pharmacology Indoles - therapeutic use Medical sciences mGluR1 Mice Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Psycholeptics: tranquillizer, neuroleptic Psychology. Psychoanalysis. Psychiatry Psychopharmacology Psychotic disorder Psychotic Disorders - drug therapy Rats Receptors, Metabotropic Glutamate - antagonists & inhibitors Receptors, Metabotropic Glutamate - metabolism Structure-Activity Relationship Psychotic disorder mGluR1 Antagonist Glutamate Group I mglu glutamate receptor Rat Rodentia Lactam mglu1 glutamate receptor Glutamate receptor Isoindole derivatives In vitro Psychosis In vivo Vertebrata Mammalia Treatment Structure activity relation Metabotropic receptor Animal Fluorine Organic compounds Pharmacokinetics Chemical synthesis
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Summary:	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 1 mg/kg in an animal model.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.07.145