Abstract 16938: IW-1973 is a Potent Soluble Guanylate Cyclase Stimulator in vitro and in vivo With Extensive Tissue Distribution

Introduction: A number of diseases including hypertension, diabetes, heart failure, and pulmonary hypertension are associated with elevated reactive oxygen species, endothelial dysfunction, and reduced nitric oxide (NO) signaling. IW-1973 is a novel clinical-stage compound that stimulates soluble guanylate (sGC), the target of NO and a key enzyme in the NO / cyclic guanosine 3’,5’-monophosphate (cGMP) signaling pathway. Methods: IW-1973 was characterized in vitro with respect to stimulation of cGMP production in HEK-293 cells endogenously expressing sGC. The effect of IW-1973 on relaxation of human resistance arteries ex vivo was determined. The relationships between oral dose, IW-1973 exposure, and hemodynamic effects were probed in normotensive rats and spontaneously hypertensive rats (SHRs). The pharmacokinetic (PK) profile of IW-1973 was determined following oral and intravenous dosing in rats, and tissue distribution was determined in steady-state rat dosing studies. Results: IW-1973 was a potent stimulator of sGC in HEK-293 cells (EC 50 197 nM, 95% CI 94.4-411 nM) in the presence of the NO donor DETA-NONOate. IW-1973 demonstrated concentration-dependent relaxation of human pre-contracted subcutaneous resistance arteries ex vivo (EC 50 34.7 nM). In vivo , IW-1973 demonstrated dose-dependent mean arterial pressure (MAP) reduction (10-30 mm Hg) in normotensive and hypertensive rats. At a 1 mg/kg dose, corresponding to a 1-hr plasma free drug concentration of 0.5 nM, MAP changes of -10.0±0.9 and -16.2±1.8 mm Hg were observed in normotensive rats and SHRs, respectively. In rat PK studies, IW-1973 had 80-102% oral bioavailability, gradual absorption (Tmax 8 h), long half-life (12-22 h), a large volume of distribution (10-11 L/kg) and was cleared hepatically. IW-1973 was determined to extensively distribute to tissues including heart, kidney, liver, and lung. Conclusions: IW-1973, a novel sGC stimulator that enhances NO signaling, is a potent vasodilator in vitro and in vivo, is orally bioavailable, and extensively distributes to tissues. These results support clinical evaluation of IW-1973 in diseases associated with impaired NO signaling.