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

摘要

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 (Ke0) for TY‐55002 was three times greater than for cinaciguat. On the other hand, there was a small difference in blood half‐life (T1/2) between the compounds. It is possible that the rapid fall in blood pressure after the initial administration of style="fixed-case">TY‐55002 and the quick recovery after cessation were due to the pharmacodynamic property of the compound. In heart failure‐model dogs, style="fixed-case">TY‐55002 and cinaciguat improved the condition to the same degree, and the short‐term action of style="fixed-case">TY‐55002 was replicated. In conclusion, style="fixed-case">TY‐55002 is a novel short‐acting style="fixed-case">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.