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

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 (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.

Soluble guanylyl cyclase stimulation and phosphodiesterase‐5 inhibition improve portal hypertension and reduce liver fibrosis in bile duct–ligated rats

“…NASH) are warranted, especially when using combinations of sGC agonists and PDE-5 inhibitors 33 or promising second-generation sGC activators with an improved pharmacokinetic profile. 34 In conclusion, our study supports the therapeutic potential of the sGC stimulator RIO and the PDE-5 inhibitor TADA for cirrhotic PHT. Both drugs decreased PP by reducing IHVR via the promotion of sinusoidal vasodilation and a reduction of liver fibrogenesis.…”

“…Further experimental studies in other chronic liver disease settings (i.e. NASH) are warranted, especially when using combinations of sGC agonists and PDE‐5 inhibitors 33 or promising second‐generation sGC activators with an improved pharmacokinetic profile 34 …”

Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO

“…Our results therefore indicate the need of caution with drugs that chronically activate the NO-sGC-PRKG signaling pathway, since they may be detrimental to aortic homeostasis. These drugs include advanced sGC stimulators such as Vericiguat (BAY 1021189) and Riociguat (BAY 63-2521), the latter having received FDA approval for pulmonary hypertension and heart failure 50,51 , as well as novel short-acting sGC activators that lack hypotensive side effects, such as TY-55002, a candidate for the treatment of patients with acute decompensated heart failure 52 . Seemingly in conflict with our results, increased NO production by constitutively active Nos3 has been reported to exert a beneficial effect on the aorta in MFS mice 53 .…”

The NO–cGMP–PKG pathway in skeletal remodeling

“…Currently, an sGC agonist, riociguat, is approved by the FDA for treating pulmonary hypertension. It has shown a favorable safety profile and is well tolerated, with hypotension and syncope as the most frequent side effect 53 . A randomized, controlled, phase IIb trial of cinaciguat use for acute heart failure syndromes showed the short‐term use of intravenous cinaciguat caused frequent hypotension without beneficial effects on respiratory and cardiac index 54 .…”