Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold.

Sharma S, Rodriguez AL, Conn PJ, Lindsley CW
Bioorg Med Chem Lett. 2008 18 (14): 4098-101

PMID: 18550372 · PMCID: PMC2533619 · DOI:10.1016/j.bmcl.2008.05.091

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a mGluR5 allosteric partial antagonist lead based on a 5-(phenylethynyl)pyrimidine scaffold. With slight structural modifications to the distal phenyl ring, analogues demonstrated a range of pharmacological activities from mGluR5 partial antagonism to full antagonism/negative allosteric modulation to positive allosteric modulation.

MeSH Terms (16)

Allosteric Regulation Allosteric Site Animals Binding, Competitive Chemistry, Pharmaceutical Drug Design Humans Inhibitory Concentration 50 Ligands Models, Chemical Pyrimidines Rats Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate Structure-Activity Relationship Time Factors

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