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

Pharmacol Res Perspect. 2019 Mar 4;7(2):e00463. doi: 10.1002/prp2.463. eCollection 2019 Apr.

Abstract

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 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.

Keywords: TY‐55002; acute decompensate heart failure; pharmacokinetic‐pharmacodynamic; soluble guanylate cyclase activator.

MeSH terms

  • Animals
  • Benzoates / pharmacology
  • Benzoates / therapeutic use
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • Female
  • Half-Life
  • Heart Failure / drug therapy*
  • Heart Failure / etiology
  • Hemodynamics / drug effects*
  • Humans
  • Hypotension / chemically induced
  • Hypotension / epidemiology*
  • Male
  • Models, Biological
  • Rats
  • Rats, Sprague-Dawley
  • Soluble Guanylyl Cyclase / metabolism
  • Time Factors
  • Treatment Outcome
  • Vasodilation / drug effects*
  • Vasodilator Agents / pharmacology*
  • Vasodilator Agents / therapeutic use

Substances

  • Benzoates
  • Vasodilator Agents
  • BAY 58-2667
  • Soluble Guanylyl Cyclase