Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified by functional HTS

  • Bioorg Med Chem Lett. 2009 Dec 1;19(23):6502-6. doi: 10.1016/j.bmcl.2009.10.059.
Ya Zhou  1 ,  Alice L Rodriguez ,  Richard Williams ,  C David Weaver ,  P Jeffrey Conn ,  Craig W Lindsley
Affiliations
  • 1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
PMID: 19875287 DOI: 10.1016/j.bmcl.2009.10.059
Abstract

This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype identified by a functional HTS approach. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and further examples of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold.