Key result
TY-55002, a novel short-acting sGC activator, demonstrated a plasma-to-effect-site transfer rate constant three times greater than cinaciguat, allowing rapid blood pressure recovery in animal models.
Why the study?
Cinaciguat development for acute decompensated heart failure was discontinued due to hypotension, prompting investigation of whether a novel short-acting sGC activator, TY-55002, could exert vasodilation without hypotension.
Does TY-55002 improve hemodynamics without excessive hypotension compared to cinaciguat in preclinical models of heart failure?
Does TY-55002 improve hemodynamics without excessive hypotension compared to cinaciguat in preclinical models of heart failure?
TY-55002 is a novel short-acting sGC activator that improves heart failure hemodynamics in animal models with a potentially lower risk of prolonged hypotension compared to cinaciguat.
Hypothesis-generating for short-acting sGC activators in HF; leaves open clinical translation of faster kinetics.
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 0 ) for TY ‐55002 was three times greater than for cinaciguat. On the other hand, there was a small difference in blood half‐life (T 1/2 ) 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.
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Sawabe et al. (2019) studied Acute decompensated heart failure (animal models). TY-55002 vs. Cinaciguat was evaluated on Vasodilation and hemodynamic effects (blood pressure, PK-PD). TY-55002, a novel short-acting sGC activator, demonstrated a plasma-to-effect-site transfer rate constant three times greater than cinaciguat, allowing rapid blood pressure recovery in animal models.
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