HEC95468, a novel soluble guanylate cyclase stimulator, shows protection in the Dahl model of cardiorenal disorder

Abstract

Nitric oxide (NO) signaling plays a vital role in the regulation of cardiovascular and renal function. As the main receptor of NO, soluble guanylate cyclase (sGC) catalyzes the production of cyclic guanosine monophosphate (cGMP) via NO-mediated activation. In conditions of cardiorenal disorder with reduced NO bioavailability, NO-independent sGC stimulation could be an effective way to restore the downstream signaling. In the present study, we aimed to investigate the effects of HEC95468 [methyl (4,6-diamino-2-(7-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl)pyrimidin-5-yl)carbamate], a clinical-stage sGC stimulator, in a rat model of cardiorenal damage. In vitro, HEC95468 was demonstrated to stimulate cGMP production with a slightly higher activity than the classical drug vericiguat. In vivo, HEC95468 was studied in the Dahl salt-sensitive (DSS) rats with a high-salt (HS) diet. HEC95468 treatment lowered the systolic and diastolic blood pressure, reduced the relative left ventricular free wall plus ventricular septum (LV + S) weight, prevented HS-induced increase of plasma NT-proANP and NP-proBNP levels, and improved left ventricular interstitial fibrosis. In terms of renal function, HEC95468 treatment decreased the urine protein creatinine ratio, reduced the serum level of KIM-1 and creatinine, as well as attenuating the progression of glomerulosclerosis, renal tubular damage and interstitial fibrosis. In addition, the survival rate was significantly improved in HEC95468-treated rats. These data suggest that HEC95468, a novel and potent sGC stimulator, demonstrates significant protective effects against cardiorenal disorder in HS-induced DSS rat model.