SGC Stimulation Results in Potent Anti‐hypertensive Effects as a Stand‐alone or Combination Therapy in the Rat

Abstract

Soluble guanylate cyclase (sGC) stimulators have the potential to treat a variety of cardiovascular diseases via the nitric oxide (NO)‐sGC‐cyclic guanosine monophosphate (cGMP) pathway. Ironwood Pharmaceuticals has synthesized a number of novel sGC stimulators with the objective of creating a once‐a‐day oral anti‐hypertensive.A screening paradigm that evaluated sGC enzyme stimulation, pharmacokinetics (PK), and pharmacodynamics (PD) identified three novel sGC stimulators that induce sustained cardiovascular effects after oral dosing. Potency against sGC was evaluated using an in vitro cell based assay that measured cGMP production. Compounds were subsequently evaluated in PK and blood pressure PD in vivo rat models. All compounds were potent stimulators of sGC in vitro (EC50 = 40‐220nM), had sustained compound exposure in vivo (Thalf 7‐12 hours) after oral dosing, and significantly decreased mean arterial blood pressure (MABP) in vivo (蠅 10mmHg) after oral dosing.The potential for sGC stimulators to work in combination with reference anti‐hypertensive therapies was assessed in our in vivo PD assay. Doses of Losartan, Atenolol, Amlodipine or each of our sGC stimulators that induced a decrease in MABP (蠅 10mmHg) when dosed alone were chosen. Combining sGC stimulators with anti‐hypertensives resulted in an additional 5‐50% decrease in MABP over either therapy given alone. These data indicate that IWP sGC stimulators possess potent anti‐hypertensive effects in the rat and that their efficacy increases when dosed in combination with standard anti‐hypertensive agents.This research was funded by Ironwood Pharmaceuticals.