Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists

Thomas J Woltering; Jürgen Wichmann; Erwin Goetschi; Frédéric Knoflach; Theresa M Ballard; Jörg Huwyler; Silvia Gatti

doi:10.1016/j.bmcl.2010.09.125

Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists

Bioorg Med Chem Lett. 2010 Dec 1;20(23):6969-74. doi: 10.1016/j.bmcl.2010.09.125. Epub 2010 Oct 21.

Authors

Thomas J Woltering¹, Jürgen Wichmann, Erwin Goetschi, Frédéric Knoflach, Theresa M Ballard, Jörg Huwyler, Silvia Gatti

Affiliation

¹ Discovery Chemistry, F. Hoffmann-La Roche Ltd, Basel, Switzerland. thomas.woltering@roche.com

PMID: 20971004
DOI: 10.1016/j.bmcl.2010.09.125

Abstract

This study completes a series of papers devoted to the characterization of the non-competitive mGluR2/3 antagonist properties of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives with particular emphasis on derivatizations compatible with brain penetration and in vivo activity. Especially the compounds bearing a para-pyridine consistently showed in vivo activity in rat behavioral models after oral administration, for example, blockade of the mGluR2/3 agonist LY354740-induced hypoactivity and improvement of a working memory deficit induced either by LY354740 or scopolamine in the delayed match to position task (DMTP). Moreover, combination studies with a cholinesterase inhibitor show apparent synergistic effects on working memory impairment induced by scopolamine.

MeSH terms

Administration, Oral
Animals
Azepines / chemical synthesis*
Azepines / chemistry
Azepines / pharmacology*
Behavior, Animal
Benzodiazepinones / chemical synthesis*
Benzodiazepinones / chemistry
Benzodiazepinones / pharmacology*
Brain / metabolism
Brain / physiopathology
Bridged Bicyclo Compounds / pharmacology
Cholinesterase Inhibitors / pharmacology
Drug Synergism
Excitatory Amino Acid Agonists / pharmacology
Excitatory Amino Acid Antagonists / chemical synthesis*
Excitatory Amino Acid Antagonists / pharmacology
Memory Disorders / chemically induced
Memory Disorders / drug therapy*
Rats
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Scopolamine / pharmacology

Substances

4-(3-(2,6-dimethylpyridin-4-yl)phenyl)-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo(b)(1,4)diazepin-2-one
Azepines
Benzodiazepinones
Bridged Bicyclo Compounds
Cholinesterase Inhibitors
Excitatory Amino Acid Agonists
Excitatory Amino Acid Antagonists
Receptors, Metabotropic Glutamate
metabotropic glutamate receptor 2
metabotropic glutamate receptor 3
Scopolamine
eglumetad