title: 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.
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.
authors.affiliation: Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Department of Neuroscience, Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. craig_lindsley@merck.com
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: David D
authors.initials: DD
authors.lastname: Wisnoski
authors.forename: William H
authors.initials: WH
authors.lastname: Leister
authors.forename: Julie A
authors.initials: JA
authors.lastname: O'brien
authors.forename: Wei
authors.initials: W
authors.lastname: Lemaire
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Maryann
authors.initials: M
authors.lastname: Burno
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sur
authors.forename: Gene G
authors.initials: GG
authors.lastname: Kinney
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Pettibone
authors.forename: Philip R
authors.initials: PR
authors.lastname: Tiller
authors.forename: Sheri
authors.initials: S
authors.lastname: Smith
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Joel R
authors.initials: JR
authors.lastname: Huff
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; D014150:Antipsychotic Agents; D001549:Benzamides; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid