Dioxotriazine derivatives as a new class of P2X3 receptor antagonists: Identification of a lead and initial SAR studies.

[Display omitted] P2X 3 receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X 3 receptor antagonists for the treatment of chronic pain or cough. To identify a P2X 3 lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine derivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead compound 1 which had a moderate inhibitory effect on P2X 3 receptors (IC 50 , 128 nM). Further improvement of the potency and PK profiles of this lead compound finally led to the selected compound 74 (P2X 3 IC 50 , 16.1 nM; P2X 2/3 IC 50 , 2931 nM), which demonstrated a strong analgesic effect against allodynia on oral administration in the rat partial sciatic nerve ligation model of neuropathic pain (ED 50 , 3.1 mg/kg). [ABSTRACT FROM AUTHOR]