Identification and SAR of novel diaminopyrimidines. Part 2: The discovery of RO-51, a potent and selective, dual P2X3/P2X2/3 antagonist for the treatment of pain

The purinoceptor subtypes P2X3 and P2X2/3 have been shown to play a pivotal role in models of various pain conditions. Identification of a potent and selective dual P2X3/P2X2/3 diaminopyrimidine antagonist RO-4 prompted subsequent optimization of the template. This paper describes the SAR and optimization of the diaminopyrimidine ring and particularly the substitution of the 2-amino group. The discovery of the highly potent and drug-like dual P2X3/P2X2/3 antagonist RO-51 is presented.

Graphical abstractThis paper describes the SAR and optimization of diaminopyrimidine template based P2X3/P2X2/3 antagonists. Discovery and the synthesis a highly potent and drug-like dual P2X3/P2X2/3 antagonists RO-51 is presented.Figure optionsDownload full-size imageDownload as PowerPoint slide