There is a potential role of the urotensinergic system in pulmonary diseases and in particular, urotensin II (UII) was identified as a potent spasmogen in airway smooth muscle. Moreover, the broad range of action of UII as a potent mediator of the mitogenic, angiogenic and inflammatory responses triggered speculations that the urotensin-II receptor (UT) might have a role in the pathogenesis and the progression of pulmonary arterial hypertension (PAH).
Indeed, the potential therapeutic role of blocking the urotensinergic system was recently suggested after observing that urantide, a UT orthosteric antagonist, and palosuran, a non-peptide UT antagonist, could alleviate monocrotaline (MCT)-induced PAH. Unfortunately, the lack of efficacy observed with palosuran in patients with diabetic nephropathy and the low efficacy partial agonist profile of urantide have limited their therapeutic potential. However, owing to its healing effect on hemodynamic, histological, and biochemical parameters of MCT-induced PAH, UT modulators are believed to be an optional treatment alternative for PAH.
We have UT ligands that can selectively modulate UII- or urotensin related peptide (URP)-associated biological activities. This novel pharmacological characteristic will bring new insights regarding the potential of the urotensinergic system for the treatment of UT-associated diseases. Studies are planned to evaluate the UT modulators in a MCT-induced PAH model.