P2X3 receptor is an ion channel coupled receptor, activated by ATP, and mainly located in peripheral sensory neuron.  P2X3 receptor antagonists reportedly show analgesic effects in neuropathic and inflammatory pain models.  To discover P2X3 receptor antagonists of novel chemotype, we performed high throughput screening of chemical library using FLIPR Ca-influx assay system. As a consequence, hit compound, which has pyrrolinone skeleton, was identified.  We performed the Hit to Lead SAR from the hit compound, and obtained lead compound with strong inhibitory effect on P2X3 receptor (IC50: 25 nM).  Further improvement of the potency and PK profiles of lead compound finally led to the discovery of best compound, which demonstrated outstandingly strong analgesic effect with oral administration against hyperalgesia in the partial sciatic nerve ligation model for neuropathic pain.  A docking study with the compounds and an effective homology model of human P2X3 is also presented.

Novel series P2X3 receptor antagonists: Discovery of potent and orally efficacious pyrrolinone derivatives

245th National Meeting (2013)

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