Cinaciguat hydrochloride

In Vitro

In platelets, Cinaciguat (BAY 58-2667) is a potent GC activator (EC₅₀ 15 nM) but the maximum effect is only about 1% of that achievable with NO. Concentration-response curves for Cinaciguat are constructed after 1 min exposure in the presence of sildenafil. Without ODQ, the EC₅₀ is 18 nM, and in the presence of ODQ the potency of Cinaciguat is not significantly different, the EC₅₀ being 13 nM. The potency of Cinaciguat in platelets (EC₅₀ 15 nM) is very similar to estimates made on purified recombinant GC. Cinaciguat at a maximally effective concentration of 1 μM stimulates control GC activity to about 25% of that observed with NO and, contrasting with the stimulation by NO, this level of activity remained constant as the proportion of ODQ-pretreated GC is increased.

In Vivo

Administration of Cinaciguat decreased BP and increased HR in both apo-sGC mice and WT mice. In fact, the BP-lowering effect of Cinaciguat in apo-sGC mice is significantly greater and longer lasting than in WT mice. In addition, Cinaciguat decreased BP in apo-sGC mice at concentrations that did not affect BP in WT mice. Furthermore, the IC₅₀ values for Cinaciguat-induced ex vivorelaxation of precontracted aortas are threefold lower in apo-sGC mice than in WT mice (IC₅₀=0.2 nM and 0.7 nM, respectively). Together, our results suggest that sGC activators like Cinaciguat but not sGC stimulators like BAY 41-2272 activate apo-sGC. In addition, the observation that Cinaciguat can modulate vasorelaxation and BP in WT mice suggests that even in healthy mice, a subset of the available sGC pool is haem-free and responsive to sGC activators

NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle.[Pubmed:12086987]

Br J Pharmacol. 2002 Jul;136(5):773-83.

1. Soluble guanylyl cyclase (sGC) is the only proven receptor for the ubiquitous biological messenger nitric oxide (NO) and is intimately involved in many signal transduction pathways, most notably in regulating vascular tone and platelet function. sGC is a heterodimeric (alpha/ss) protein that converts GTP to cyclic GMP; NO binds to its prosthetic haem group. Here, we report the discovery of a novel sGC activating compound, its interaction with a previously unrecognized regulatory site and its therapeutic implications. 2. Through a high-throughput screen we identified BAY 58-2667, an amino dicarboxylic acid which potently activates sGC in an NO-independent manner. In contrast to NO, YC-1 and BAY 41-2272, the sGC stimulators described recently, BAY 58-2667 activates the enzyme even after it has been oxidized by the sGC inhibitor ODQ or rendered haem deficient. 3. Binding studies with radiolabelled BAY 58-2667 show a high affinity site on the enzyme. 4. Using photoaffinity labelling studies we identified the amino acids 371 (alpha-subunit) and 231 - 310 (ss-subunit) as target regions for BAY 58-2667. 5. sGC activation by BAY 58-2667 results in an antiplatelet activity both in vitro and in vivo and a potent vasorelaxation which is not influenced by nitrate tolerance. 6. BAY 58-2667 shows a potent antihypertensive effect in conscious spontaneously hypertensive rats. In anaesthetized dogs the hemodynamic effects of BAY 58-2667 and GTN are very similar on the arterial and venous system. 7. This novel type of sGC activator is a valuable research tool and may offer a new approach for treating cardiovascular diseases.

Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels.[Pubmed:16955146]

J Clin Invest. 2006 Sep;116(9):2552-61.

ROS are a risk factor of several cardiovascular disorders and interfere with NO/soluble guanylyl cyclase/cyclic GMP (NO/sGC/cGMP) signaling through scavenging of NO and formation of the strong oxidant peroxynitrite. Increased oxidative stress affects the heme-containing NO receptor sGC by both decreasing its expression levels and impairing NO-induced activation, making vasodilator therapy with NO donors less effective. Here we show in vivo that oxidative stress and related vascular disease states, including human diabetes mellitus, led to an sGC that was indistinguishable from the in vitro oxidized/heme-free enzyme. This sGC variant represents what we believe to be a novel cGMP signaling entity that is unresponsive to NO and prone to degradation. Whereas high-affinity ligands for the unoccupied heme pocket of sGC such as zinc-protoporphyrin IX and the novel NO-independent sGC activator 4-[((4-carboxybutyl){2-[(4-phenethylbenzyl)oxy]phenethyl}amino) methyl [benzoic]acid (BAY 58-2667) stabilized the enzyme, only the latter activated the NO-insensitive sGC variant. Importantly, in isolated cells, in blood vessels, and in vivo, BAY 58-2667 was more effective and potentiated under pathophysiological and oxidative stress conditions. This therapeutic principle preferentially dilates diseased versus normal blood vessels and may have far-reaching implications for the currently investigated clinical use of BAY 58-2667 as a unique diagnostic tool and highly innovative vascular therapy.

Probing the presence of the ligand-binding haem in cellular nitric oxide receptors.[Pubmed:18204474]

Br J Pharmacol. 2008 Apr;153(7):1495-504.

BACKGROUND AND PURPOSE: Nitric oxide (NO) acts on receptors coupled to guanylyl cyclase (GC), leading to cGMP accumulation. The NO binding site is a haem group, oxidation or loss of which diminishes NO-stimulated activity. Agonists reportedly engaging both these NO-insensitive forms have emerged. Here we characterize the effect of a prototype compound (BAY 58-2667) and use it to assess the haem status of cellular GC. EXPERIMENTAL APPROACH: GC activity measurements were made on the purified protein and on rat platelets. KEY RESULTS: Experiments on purified GC showed that the target for BAY 58-2667 is the haem-free GC, not the haem-oxidized form. The efficacy of BAY 58-2667 was about half that shown normally by NO. In platelets, BAY 58-2667 was a potent GC activator (EC50 approximately 15 nM) but the maximum effect was only about 1% of that achievable with NO. Nevertheless, it was enough to evoke cGMP-dependent protein phosphorylation. Profound (85 %) desensitization of NO-evoked GC activity did not alter the effectiveness of BAY 58-2667. Haem oxidation, however, increased the efficacy of BAY 58-2667 by 22-fold, implying that about half the cellular GC was then haem-free. Oxidation appeared to enhance the rate of haem dissociation from purified GC. CONCLUSIONS AND IMPLICATIONS: Compounds such as BAY 58-2667 are useful for probing the occupancy of the haem pocket of NO receptors in cells but not for distinguishing oxidized from reduced haem. In vivo, such compounds are likely to be particularly effective in conditions where there is deficient haem incorporation or enhanced haem loss.

Potent soluble guanylyl cyclase (sGC) activator,Cinaciguat hydrochloride is a potent soluble guanylate cyclase (GC) activator with EC₅₀ of 15 nM in platelets.

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