The P2X3 receptor is an ATP-gated ion channel expressed on primary afferent neurons that sense painful stimuli (nociceptors), with limited receptor expression in other tissues. This selective expression pattern makes the P2X3 receptor an attractive analgesic target with the potential to provide a safe treatment of chronic pain states such as occurs in osteoarthritis (OA). The lead optimization strategy to address shortcomings of the 1<sup>st</sup> generation preclinical lead compound will be presented. These studies were directed at identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first generation lead.

Discovery of second generation P2X3 receptor antagonists for the treatment of chronic pain

249th National Meeting (2015)

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