sGC Stimulator Efficacy Beyond Blood Pressure in Dahl‐Salt Sensitive Model of Hypertension

Soluble guanylate cyclase (sGC) is an important intracellular receptor that can be activated by sGC stimulators to produce cyclic guanosine monophosphate (cGMP)protein kinase G (PKG) mediated effects. We have identified a novel series of sGC stimulators that decreased blood pressure (BP) in rats in a dose‐dependent manner at oral doses between 1‐10 mg/kg. These compounds possess a rat pharmacokinetic profile consistent with predicted once daily administration in humans. In this study we evaluated IWP‐121 in the Dahl Salt‐Sensitive (DSS) model of hypertension. Male DSS rats received 2 weeks of high‐salt diet prior to high salt plus compound for 6 additional weeks. Compounds were tested at doses of 1, 3, and 10 mg/kg/day eq in the chow (n=8/group) using Losartan as a positive control at a dose of 30 mg/kg/day eq in the water and compared to a high‐salt (hs) control group who received high salt diet for 8 weeks. IWP‐121 dose dependently decreased mean BP at week 8 with a maximal effect of 49 mmHg at the 10mg/kg dose. In comparison, losartan reduced mean BP by 27 mmHg. Both IWP‐121 (at all doses tested) and losartan had statistically significant effects on heart hypertrophy compared with the high‐salt (HS) group (3.5± 0.1 vs 4.5 ±0.3 g/Kg; p<0.001). IWP‐121 was efficacious at decreasing microalbuminaria in the urine (an indicator of kidney end organ protection) and serum biomarkers known to be involved in inflammatory and fibrotic processes (TIMP‐1, OPN and MCP‐1) in a dose‐dependent manner. In summary, IW‐121 demonstrated a potent anti‐hypertensive effect, additional effects in end organ protection, and effects on biomarkers consistent with anti‐fibrotic/anti‐inflammatory activity.