The Novel, Clinical Stage Soluble Guanylate Cyclase Activator BI 685509 Protects from Disease Progression in Models of Renal Injury and Disease.

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.