HW091077

The P2X3 receptor is an ATP-activated ion channel primarily expressed on peripheral sensory neurons. Its activation triggers cough reflex pathways, making it an attractive target for treating chronic cough and the discovery of P2X3 receptor antagonist has been a long-term pursuit by academia and pharmaceutical companies. However, preliminary antagonists have been hampered by taste disturbances or drug-induced liver injury. Our strategy described herein are maintaining a moderate selectivity between P2X3 and P2X2/3 receptors and replacing the metabolically labile motif with 3-methylbutan-2-ol. These discovery efforts lead to the identification of HW091077, a P2X3 receptor antagonist with an optimal balance of potency, selectivity, PK and metabolic properties that has advanced into clinical trials for the treatment of chronic cough.