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

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.

Graphical abstractThe synthesis and SAR of a mGluR5 allosteric partial antagonist lead 8 is described. We have identified ‘molecular switches’ on the distal phenyl ring that modulate modes of efficacy from mGluR5 partial antagonism in 8, to full non-competitive antagonism 12a to positive allosteric modulation 12h by the addition of a 3- or 4-methyl group, respectively.Figure optionsDownload full-size imageDownload as PowerPoint slide