G-Yoon Jamie Im

Discovery of IWP-051, a Novel Orally Bioavailable sGC Stimulator with Once-Daily Dosing Potential in Humans

In recent years, soluble guanylate cyclase (sGC, EC 4.6.1.2) has emerged as an attractive therapeutic target for treating cardiovascular diseases and diseases associated with fibrosis and end-organ failure. Herein, we describe our design and synthesis of a series of 4-hydroxypyrimidine sGC stimulators starting with an internally discovered lead. Our efforts have led to the discovery of IWP-051, a molecule that achieves good alignment of potency, stability, selectivity, and pharmacodynamic effects while maintaining favorable pharmacokinetic properties with once-daily dosing potential in humans.

Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-Inflammatory, and Antifibrotic Effects in Preclinical Models of Disease

Soluble guanylate cyclase (sGC), a key signal-transduction enzyme, increases the conversion of guanosine-5′-triphosphate to cGMP upon binding of nitric oxide (NO). Endothelial dysfunction and/or reduced NO signaling have been implicated in cardiovascular disease pathogenesis and complications of diabetes and have been associated with other disease states and aging. Soluble guanylate cyclase (sGC) stimulators are small-molecule drugs that bind sGC and enhance NO-mediated cGMP signaling. The pharmacological characterization of IW-1973 [1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl) pyrimidin-4-yl)amino)methyl)propan-2-ol], a novel clinical-stage sGC stimulator under clinical investigation for treatment of heart failure with preserved ejection fraction and diabetic nephropathy, is described. In the presence of NO, IW-1973 stimulated sGC in a human purified enzyme assay and a HEK-293 whole cell assay. sGC stimulation by IW-1973 in cells was associated with increased phosphorylation of vasodilator-stimulated phosphoprotein. IW-1973, at doses of 1–10 mg/kg, significantly lowered blood pressure in normotensive and spontaneously hypertensive rats. In a Dahl salt-sensitive hypertension model, IW-1973 significantly reduced blood pressure, inflammatory cytokine levels, and renal disease markers, including proteinuria and renal fibrotic gene expression. The results were affirmed in mouse lipopolysaccharide-induced inflammation and rat unilateral ureteral obstruction renal fibrosis models. A quantitative whole-body autoradiography study of IW-1973 revealed extensive tissue distribution and pharmacokinetic studies showed a large volume of distribution and a profile consistent with predicted once-a-day dosing in humans. In summary, IW-1973 is a potent, orally available sGC stimulator that exhibits renoprotective, anti-inflammatory, and antifibrotic effects in nonclinical models.

Discovery of IWP-051, a novel orally bioavailable soluble guanylate cyclase stimulator with sustained and dose-dependent hemodynamic effects.

Discovery of IWP-051, a novel orally bioavailable soluble guanylate cyclase stimulator with sustained and dose-dependent hemodynamic effects Takashi Nakai, Nicholas R Perl, Rajesh R Iyengar, Ara Mermerian, G-Yoon J Im, Thomas W-H Lee, Glen R Rennie, James Jia, Paul A Renhowe, Timothy C Barden, James E Sheppeck II, Karthik Iyer, Joon Jung, G Todd Milne, Chrissie Segal, Kimberly Long, Joy Miyashiro, Sylvie Bernier, Sarah Jacobson, Jenny Tobin, Courtney Shea, Peter Germano, Yueh-tyng Chien, Daniel Zimmer

Concomitant administration of sGC stimulators with common classes of anti-hypertensive agents results in increased efficacy in spontaneously hypertensive rats

Background Soluble guanylate cyclase (sGC) stimulators demonstrate smooth muscle relaxation and vasodilation via the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway. A novel class of sGC stimulators, the pyrazole-pyrimidines, was synthesized with the objective of creating a potent, once-a-day (QD) oral treatment for cardiovascular diseases. Several compounds from this class were identified as potent stimulators of sGC in vitro (EC50 = 40-287 nM). These compounds were evaluated in pharmacokinetic (PK) and blood pressure pharmacodynamics (PD) in vivo rat and dog models and were shown to exhibit sustained compound exposure (Thalf = >7 hours in preclinical species) after oral dosing, predicting QD dosing in humans. Further, they significantly decreased mean arterial blood pressure (MAP (≥ 10mmHg) after oral dosing. The potential for sGC stimulators to work in combination with reference antihypertensive therapies was assessed in an in vivo PD assay in a spontaneous hypertensive rat (SHR) model. Doses of losartan, atenolol, amlodipine, and our sGC stimulators that induced an effect (< 30mmHg) on MAP were chosen. IWP-121, a representative sGC stimulator, was shown to provide additional MAP lowering effects when combined with losartan, atenolol, or amlodipine, resulting in an increase in overall blood pressure effects between 5-50%. By linking compound concentration to blood pressure change for each compound alone and in combination, we were able to assess the PK/PD relationships for the individual and combined effects.

IWP-121: a novel sGC stimulator that reduces blood pressure and exhibits anti-fibrotic and anti-inflammatory activities in the Dahl Salt-Sensitive rat model

Background Soluble guanylate cyclase (sGC) is an intracellular receptor that can be activated by nitric oxide (NO) and sGC stimulators to produce cyclic guanosine monophosphate (cGMP), thereby modulating a number of downstream cellular and physiological responses including phosphorylation of VASP and vasodilation. In the Dahl Salt-Sensitive (DSS) rat model of hypertension, cGMP production by sGC is decreased, most likely due to reactive oxygen species (ROS) converting NO to peroxynitrite, resulting in depleted pools of NO available to bind to sGC. In this study we evaluated the efficacy of a novel sGC stimulator (IWP-121) in the DSS model. Male DSS rats (230-270 grams) received high-salt diet (8% NaCl) for 2 weeks followed by high salt plus compound for 6 additional weeks. IWP-121 was administered at doses of 1, 3, and 10 mg/kg/ day in the chow (n=8/group). Losartan (30 mg/kg/day in the water) was used as a positive control, in addition to both High Salt (HS) and Normal Salt (NS). All groups were compared to HS control group for analyses. IWP-121 dose dependently decreased mean blood pressure (MAP) throughout the study. Additionally, IWP-121 (at all doses tested) and losartan had statistically significant effects on decreasing heart hypertrophy and plasma NT-proBNP but only IWP-121 had an effect on attenuating liver hypertrophy. IWP-121 decreased microalbuminuria (an indicator of kidney end organ damage) as well as attenuated serum biomarkers known to be involved in inflammatory and fibrotic processes. Conclusion In the rat DSS model of hypertension, there is a decrease in cGMP levels most likely due to the inactivation of endogenous NO by ROS. The sGC stimulator IWP-121, when administered in the diet exhibited sustained dosedependent reduction in blood pressure. Additionally, IWP-121 attenuated heart and liver hypertrophy and reduced NT-proBNP, a biomarker of heart failure. The compound reduced levels of biomarkers for inflammation and fibrosis, and demonstrated renal end organ protection. sGC stimulators, like IWP-121 may have broad therapeutic application by modulating multiple relevant therapeutic endpoints including blood pressure, hypertrophy, inflammation, and fibrosis.