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.
Zhijian Zhao  1 ,  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
Affiliations
  • 1. Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA. [email protected]
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.