Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a dual P2X3/P2X2/3 antagonist for the treatment of pain

Abstract P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X 3 and P2X 2/3 receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X 3 /P2X 2/3 antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X 3 /P2X 2/3 antagonist.