A novel soluble guanylate cyclase activator with reduced risk of hypotension by short-acting vasodilation.

Cinaciguat, a soluble guanylate cyclase (sGC) activator, was under clinical development for use in acute decompensated heart failure (ADHF), but was discontinued due to occurrence of hypotension. We hypothesized that short-term activation of sGC in ADHF patients would exert a vasodilative effect without hypotension irrespective of disease state, using a novel short-acting sGC activator, TY-55002. The objective of this study was to investigate the vasodilation and hemodynamic effects of TY-55002 in comparison with those of cinaciguat. TY-55002 and cinaciguat activated both normal and heme-oxidized sGC in a dose-dependent manner and caused rapid relaxation of phenylephrine-contracted rat aorta. However, TY-55002 had a milder effect than cinaciguat in enhancing the dose-activity response between normal and oxidized sGC. Therefore, we suggest that the pharmacological effect of TY-55002 is less subject than cinaciguat to oxidative stress associated with complications such as cardiovascular disease or diabetes. In normal dogs, the effects of intravenous TY-55002 or cinaciguat on blood pressure were evaluated in conjunction with the plasma concentrations of the compounds, and pharmacokinetic (PK)-pharmacodynamic (PD) analyses were carried out. The plasma-to-effect-site transfer rate constant (Ke) for TY-55002 was three times greater than for cinaciguat. On the other hand, there was a small difference in blood half-life (T) between the compounds. It is possible that the rapid fall in blood pressure after the initial administration of TY-55002 and the quick recovery after cessation were due to the pharmacodynamic property of the compound. In heart failure-model dogs, TY-55002 and cinaciguat improved the condition to the same degree, and the short-term action of TY-55002 was replicated. In conclusion, TY-55002 is a novel short-acting sGC activator, which offers the possibility of easy dose management without excessive hypotension. It therefore holds potential to serve as an innovative drug in the pharmacotherapy of ADHF.