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.
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.
Lindsley
Craig W
CW
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
Wisnoski
David D
DD
Leister
William H
WH
O'brien
Julie A
JA
Lemaire
Wei
W
Williams
David L
DL
Burno
Maryann
M
Sur
Cyrille
C
Kinney
Gene G
GG
Pettibone
Doug J
DJ
Tiller
Philip R
PR
Smith
Sheri
S
Duggan
Mark E
ME
Hartman
George D
GD
Conn
P Jeffrey
PJ
Huff
Joel R
JR
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
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