We report on the optimisation strategy applied to a tetrahydropyrido[4,3-d]pyrimidine dual P2X3 / P2X2/3 receptor antagonist hit, identified from a purinergic focused HTS campaign. SAR and DMPK parameters, including aqueous solubility; protein binding; oral bioavailability and hERG blockade were optimised and the key P2X3 / P2X2/3 SAR presented. Several advanced Lead compounds were identified that underwent detailed electrophysiology, DMPK and in vivo efficacy testing (inflammatory and neuropathic pain). Here we present the data for one such Lead Compound that warrants further Early Development Candidate (EDC) profiling and continued evaluation as a potential treatment of pain and urinary dysfunction.

Development of novel P2X3 / P2X2/3 receptor antagonists for the treatment of pain and urinary dysfunction

243rd National Meeting (2012)

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