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Abstract: Despite the extensive literature describing the role of the ATP-gated P2X3 receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X3 antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]