Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA

Zhijian Zhao; David D Wisnoski; Julie A O'Brien; Wei Lemaire; David L Williams Jr; Marlene A Jacobson; Marion Wittman; Sookhee N Ha; Herve Schaffhauser; Cyrille Sur; Doug J Pettibone; Mark E Duggan; P Jeffrey Conn; George D Hartman; Craig W Lindsley

doi:10.1016/j.bmcl.2006.11.081

Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA

Bioorg Med Chem Lett. 2007 Mar 1;17(5):1386-91. doi: 10.1016/j.bmcl.2006.11.081. Epub 2006 Dec 3.

Authors

Zhijian Zhao¹, David D Wisnoski, Julie A O'Brien, Wei Lemaire, David L Williams Jr, Marlene A Jacobson, Marion Wittman, Sookhee N Ha, Herve Schaffhauser, Cyrille Sur, Doug J Pettibone, Mark E Duggan, P Jeffrey Conn, George D Hartman, Craig W Lindsley

Affiliation

¹ Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. zhijian_zhao@merck.com

PMID: 17210250
DOI: 10.1016/j.bmcl.2006.11.081

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.

MeSH terms

Allosteric Regulation*
Allosteric Site
Animals
Benzamides / chemistry*
Benzamides / pharmacology*
Humans
Phthalimides / chemistry*
Phthalimides / pharmacology*
Rats
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate / drug effects*
Structure-Activity Relationship

Substances

Benzamides
GRM5 protein, human
Grm5 protein, rat
N-(4-chloro-2-((1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl)phenyl)-2-hydroxybenzamide
Phthalimides
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate