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

AUTHORS

Zhou YYa , Rodriguez AL Alice L , Williams R Richard , Weaver CD C David , Conn PJ P Jeffrey , Lindsley CW Craig W . Bioorganic & medicinal chemistry letters. 2009 12 1; 19(23). 6502-6

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.

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.