Discovery of Molecular Switches that Modulate Modes of mGlu5 Pharmacology In Vitro and In Vivo Within a Series of Functionalized, Regioisomeric 2- and 5-(Phenylethynyl) Pyrimidines

This Letter describes the synthesis and SAR of a series of analogs of the mGlu 5 partial antagonist 5-(phenylethynyl)pyrimidine. New molecular switches are identified that modulate the pharmacological activity of the lead compound. Slight structural modifications around the proximal pyrimidine ring...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2009-07, Vol.52 (14), p.4103-4106
Main Authors: Sharma, Sameer, Kedrowski, Jeffrey, Rook, Jerri M., Smith, Randy L., Jones, Carrie K., Rodriguez, Alice L., Conn, P. Jeffrey, Lindsley, Craig W.
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:This Letter describes the synthesis and SAR of a series of analogs of the mGlu 5 partial antagonist 5-(phenylethynyl)pyrimidine. New molecular switches are identified that modulate the pharmacological activity of the lead compound. Slight structural modifications around the proximal pyrimidine ring change activity of the partial antagonist lead to that of potent and selective full negative allosteric modulators and positive allosteric modulators, that demonstrate in vivo efficacy in rodent models for anxiolytic activity and antipsychotic, respectively.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900654c