Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo

Craig W Lindsley; David D Wisnoski; William H Leister; Julie A O'brien; Wei Lemaire; David L Williams Jr; Maryann Burno; Cyrille Sur; Gene G Kinney; Doug J Pettibone; Philip R Tiller; Sheri Smith; Mark E Duggan; George D Hartman; P Jeffrey Conn; Joel R Huff

doi:10.1021/jm049400d

Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo

J Med Chem. 2004 Nov 18;47(24):5825-8. doi: 10.1021/jm049400d.

Authors

Craig W Lindsley¹, David D Wisnoski, William H Leister, Julie A O'brien, Wei Lemaire, David L Williams Jr, Maryann Burno, Cyrille Sur, Gene G Kinney, Doug J Pettibone, Philip R Tiller, Sheri Smith, Mark E Duggan, George D Hartman, P Jeffrey Conn, Joel R Huff

Affiliation

¹ Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Department of Neuroscience, Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. [email protected]

PMID: 15537338
DOI: 10.1021/jm049400d

Abstract

This report describes the discovery of the first centrally active allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g., 8) have been identified as a novel class of potent positive allosteric modulators of mGluR5 that potentiate the response to glutamate. An iterative analogue library synthesis approach provided potentiators with excellent potency and selectivity for mGluR5 (vs mGluRs 1-4, 7, 8). Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotics based on the NMDA hypofunction model for schizophrenia.

MeSH terms

Allosteric Regulation
Animals
Antipsychotic Agents / chemical synthesis
Antipsychotic Agents / chemistry
Antipsychotic Agents / pharmacology
Benzamides / chemical synthesis*
Benzamides / chemistry
Benzamides / pharmacology
Brain / metabolism
CHO Cells
Cricetinae
Cricetulus
Glutamic Acid / pharmacology
Humans
In Vitro Techniques
Pyrazoles / chemical synthesis*
Pyrazoles / chemistry
Pyrazoles / pharmacology
Rats
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate / drug effects*
Receptors, Metabotropic Glutamate / physiology
Reflex, Startle / drug effects
Structure-Activity Relationship

Substances

3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
Antipsychotic Agents
Benzamides
GRM5 protein, human
Grm5 protein, rat
Pyrazoles
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate
Glutamic Acid