Cinaciguat (hydrochloride)

Cinaciguat hydrochloride is a potent soluble guanylate cyclase (GC) activator with EC₅₀ of 15 nM in platelets. IC50 & Target: EC50:15 nM (Guanylate cyclase)^[1] 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^[1]. 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^[2].