title: Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. zhijian_zhao@merck.com
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Zhao
authors.forename: David D
authors.initials: DD
authors.lastname: Wisnoski
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: Marlene A
authors.initials: MA
authors.lastname: Jacobson
authors.forename: Marion
authors.initials: M
authors.lastname: Wittman
authors.forename: Sookhee N
authors.initials: SN
authors.lastname: Ha
authors.forename: Herve
authors.initials: H
authors.lastname: Schaffhauser
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sur
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Pettibone
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: 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
chemical_list: 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