purinergic receptor (ion channel) antagonist
up to 300 mg PO QD, phase IIb, chronic cough
from opt. of prior P2X3 antagonist
Bioorganic and Medicinal Chemistry Letters
Shionogi
The Shionogi P2X3 ligand-gated ion channel antagonist, sivopixant (S-600918), is an oral Ph. II candidate for refractory chronic cough, which recently completed a its Ph. IIb study, overcoming the projected high dose requirement of a prior preclinical candidate. The molecule has a very polar core structure with both a dioxotriazine and carboxylic acid, yet is highly bioavailable. From a chemistry perspective, it is an interesting example where adding another aromatic heterocycle at a late stage of optimization led to a significant lowering of human dose projection, whereas typically at a late stage adding large new groups tends to be avoided.