Abstract

Activation of soluble guanylate cyclase (sGC) to restore cyclic guanosine monophosphate (cGMP) and improve functionality of nitric oxide (NO) pathways impaired by oxidative stress is a potential treatment for diabetic and chronic kidney disease. We report the pharmacology of BI 685509, a novel, orally active small molecule sGC activator with disease modifying potential. BI 685509 and human sGC α1/β1 heterodimer containing a reduced heme group, produced concentration-dependent increases in cGMP that were elevated modestly by NO whereas heme-free sGC and BI 685509 greatly enhanced cGMP with no effect of NO. BI 685509 increased cGMP in human and rat platelet-rich plasma treated with the heme-oxidant ODQ; respective EC₅₀ values were 467 nM and 304 nM. In conscious telemetry-instrumented rats, BI 685509 did not effect mean arterial pressure (MAP) or heart rate (HR) at 3 and 10 mg/kg (p.o.) whereas 30 mg/kg decreased MAP and increased HR. Ten-days of BI 685509 at supratherapeutic doses (60 or 100 mg/kg po, qd) attenuated MAP and HR responses to a single 100 mg/kg challenge. In the ZSF1 rat model, BI 685509 (1, 3, 10, 30 mg/kg/day qd) co-administered with enalapril (3 mg/kg/day) dose-dependently reduced proteinuria and incidence of glomerular sclerosis; MAP was modestly reduced at the higher doses vs. enalapril. In the 7-day rat UUO model, BI 685509 dose-dependently reduced tubulointerstitial fibrosis (p<0.05 at 30 mg/kg). In conclusion, BI 695509 is a potent, orally bioavailable sGC activator with clear renal protection and anti-fibrotic activity in preclinical models of kidney injury and disease.

Significance Statement BI 685509 is a novel small sGC molecule activator that exhibits an in vitro profile consistent with that of an sGC activator. In BI 685509 reduced proteinuria and glomerulosclerosis in the ZSF1 rat, a model of DKD, and reduced tubulointerstitial fibrosis in a rat 7-Day UUO model. Thus, BI 685509 is a promising new therapeutic agent and is currently in Phase II clinical trials for CKD and DKD.