molecules of the month

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.