Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate cyclase stimulator

Stimulation of Erythrocyte Soluble Guanylyl Cyclase Induces cGMP Export and Cardioprotection in Type 2 Diabetes

“…Postischemic recovery of LVDP was impaired and infarct size was larger in hearts given RBCs from patients with T2D compared with hearts given RBCs from healthy subjects ( Figures 1A and 1B ). Incubation of RBCs either from patients with T2D or from healthy controls with the ferrous-dependent sGC stimulator CYR715 24 significantly enhanced recovery of LVDP ( Figures 2A and 2B ). The percentage improvement in postischemic recovery of LVDP induced by sGC stimulation in RBCs was significantly greater in hearts given RBCs from patients with T2D than in those given RBCs from healthy controls ( P = 0.002), resulting in comparable postischemic cardiac function in hearts exposed to RBCs from healthy subjects and patients with T2D after incubation with the sGC stimulator.…”

“…Thus, off-target effects of the drugs used in the current study cannot be excluded, although the sGC stimulator is known to be highly selective. 24 The use of genetic deletion or gene silencing is unfortunately not possible when using human RBCs. Moreover, it remains to be established how cGMP is transmitted from the RBCs to the target cell to exert the protective effects.…”

Decoding signaling mechanisms: unraveling the targets of guanylate cyclase agonists in cardiovascular and digestive diseases

“…CYR715, first described by Rennie et al, is a novel carboxylic acid-containing sGC stimulator that exhibited similar dose-dependent hemopharmacology in normotensive rats. Compared to the previously described IWP-051, CYR715 had a better pharmacokinetic profile in rats and exhibits similar dose-dependent hemodynamics in normotensive rats (Rennie et al, 2021). A recent study found that preincubating red blood cells from type 2 diabetes (T2D) patients with CYR715 and administering them to isolated rat hearts enhanced left ventricular diastolic pressure recovery, reduced infarct size, and mitigated endothelial dysfunction.…”