Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA.
This Letter describes, for the first time, the synthesis and SAR, developed through an iterative analog library approach, that led to the discovery of the positive allosteric modulator (PAM) of the metabotropic glutamate receptor mGluR5 CPPHA. Binding to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories.
Zhao
Zhijian
Z
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. zhijian_zhao@merck.com
Wisnoski
David D
DD
O'Brien
Julie A
JA
Lemaire
Wei
W
Williams
David L
DL
Jacobson
Marlene A
MA
Wittman
Marion
M
Ha
Sookhee N
SN
Schaffhauser
Herve
H
Sur
Cyrille
C
Pettibone
Doug J
DJ
Duggan
Mark E
ME
Conn
P Jeffrey
PJ
Hartman
George D
GD
Lindsley
Craig W
CW
D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D010797:Phthalimides / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D013329:Structure-Activity Relationship
D001549:Benzamides; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; C481448:N-(4-chloro-2-((1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl)phenyl)-2-hydroxybenzamide; D010797:Phthalimides; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate