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

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Abstract

P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X3 and P2X2/3 receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X3/P2X2/3 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 P2X3/P2X2/3 antagonist.

Graphical abstract

The discovery and structure–activity relationships of a novel series of diaminopyrimidine based dual P2X3/P2X2/3 antagonists is described.

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    These results were supported by experiments with A-317491, a potent, selective P2X3R and P2X2/3R antagonist: in a variety of animal models, pharmacological P2X3R inhibition attenuated neuropathic and chronic inflammatory pain but had no effect on nociception in models of acute or postoperative pain (Jarvis et al., 2002). Recent interest in P2XRs has led to the development of several new drug-like antagonists for P2X3Rs in the last few years (Bolcskei and Farkas, 2014; Brotherton-Pleiss et al., 2010; Cantin et al., 2012; Carter et al., 2009; Cho et al., 2013; Ford and Undem, 2013; Gever et al., 2010; Jahangir et al., 2009; Jung et al., 2013, 2017). However, to date AF-219 (formerly RO4926219) is the only P2X3R antagonist under clinical development (Abdulqawi et al., 2015; Muller, 2015).

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