R&D Department TOA EIYO LTD. Fukushima Research Laboratories Fukushima Japan.
R&D Department TOA EIYO LTD. Tokyo Research Laboratories Saitama Japan.
Pharmacol Res Perspect. 2019 Mar 4;7(2):e00463. doi: 10.1002/prp2.463. eCollection 2019 Apr.
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.
西那卡塞是一种可溶性鸟苷酸环化酶（sGC）激活剂，曾在急性失代偿性心力衰竭（ADHF）的临床试验中进行研究，但由于低血压的发生而被停用。我们假设，使用新型短效 sGC 激活剂 TY-55002，在 ADHF 患者中短期激活 sGC 将发挥血管扩张作用而不会发生低血压，无论疾病状态如何。本研究旨在比较 TY-55002 与西那卡塞的血管舒张和血液动力学作用。TY-55002 和西那卡塞均以剂量依赖性方式激活正常和血红素氧化的 sGC，并迅速松弛去氧肾上腺素收缩的大鼠主动脉。然而，与西那卡塞相比，TY-55002 增强正常和氧化 sGC 之间的剂量活性反应的作用较弱。因此，我们认为 TY-55002 的药理作用不太容易受到与心血管疾病或糖尿病等并发症相关的氧化应激的影响。在正常犬中，评估了静脉注射 TY-55002 或西那卡塞对血压的影响，并结合化合物的血浆浓度进行了药代动力学（PK）-药效学（PD）分析。TY-55002 的血浆到效应部位转移速率常数（Ke）是西那卡塞的三倍。另一方面，两种化合物的血液半衰期（T）差异很小。TY-55002 初始给药后血压迅速下降，停药后迅速恢复，这可能是由于化合物的药效学特性所致。在心力衰竭模型犬中，TY-55002 和西那卡塞改善了病情的程度相同，并且复制了 TY-55002 的短期作用。总之，TY-55002 是一种新型短效 sGC 激活剂，具有无需过度低血压即可轻松管理剂量的可能性。因此，它有可能成为 ADHF 药物治疗的创新药物。
