BLU-5937: Pioneering a Selective P2X3 Antagonist for Effective Cough Suppression without Taste Disturbance

BLU-5937 is identified as a potent and selective antagonist of the P2X3 receptor, a target implicated in the hypersensitivity of the cough reflex and chronic cough conditions. This small molecule inhibits the P2X3 receptor with high potency, as demonstrated by its IC50 values in vitro, and effectively prevents the sensitization of the cough reflex. The compound is under development for the treatment of chronic cough and has shown significant anti-tussive effects in animal models without causing taste alterations, unlike some less selective antagonists.

In vitro studies have confirmed BLU-5937's selectivity for P2X3 over P2X2/3 receptors, with respective IC50 values of 25 nM and greater than 24 μM. The compound also suppressed sensitization and activity in primary nociceptors in rat dorsal root ganglions, indicating its action through P2X3 receptor antagonism. Oral administration of BLU-5937 in guinea pigs resulted in a dose-dependent reduction of coughs induced by histamine or ATP, suggesting its potential in treating cough.

Importantly, BLU-5937 did not impact taste perception in a rat taste model at doses much higher than those required for P2X3 inhibition, highlighting its selectivity and an advantage over less selective P2X3 antagonists that can affect taste.

Pharmacokinetic assessments indicate that BLU-5937 has favorable drug-like properties, including good oral bioavailability, low clearance, no blood-brain barrier permeability, and a high safety margin. The compound is currently in Phase I clinical trials. Overall, BLU-5937's potency, selectivity, anti-tussive effects, and tolerability make it a promising candidate for the treatment of chronic cough.