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

Abstract

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)-1-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.

Pharmacokinetics, mass balance, tissue distribution, metabolism, and excretion of praliciguat, a clinical‐stage soluble guanylate cyclase stimulator in rats

“…The QWBA study revealed that praliciguat was widely distributed, which is consistent with the large volume of distribution found for praliciguat in pharmacological studies in the rat ( V ss 10.5 L/kg, 7 and with the apparent volume of distribution in the humans ( V z / F 3100‐3610 L, 8). Tissues with the highest exposure ratios relative to plasma were liver, intestines, adrenal gland, and adipose, and those with the lowest values were seminal vesicle, blood, CNS tissues, lens of the eye, and bone, there was no specific association with melanin in the skin or eye.…”

“…In addition to the anti‐inflammatory, antifibrotic, renoprotective, and hepatoprotective effects of praliciguat demonstrated in preclinical models, 7,13,14 emerging preclinical and clinical data indicate that praliciguat may have favorable effects on metabolic parameters, including cholesterol and insulin resistance 9,15,16 . These effects are of particular interest since, to our knowledge, they have not been reported for other sGC stimulators in humans and could be accentuated by the extensive tissue distribution of praliciguat.…”

“…Praliciguat has a large volume of distribution in both preclinical and clinical studies, consistent with extensive distribution to tissues 7,8 . Higher levels of drug in tissues than in the bloodstream could enhance sGC pharmacology in target organs while minimizing effects on systemic blood pressure.…”

“…For example, in a Dahl salt‐sensitive rat model of hypertension and organ damage, praliciguat‐treated animals had lower blood pressure and lower levels of inflammatory cytokines and markers of renal disease, including proteinuria and renal fibrotic gene expression 7 . Notable renoprotective effects were also observed in a rat unilateral ureteral obstruction renal fibrosis model, wherein treatment with praliciguat for 14 days following ureteral obstruction resulted in reductions in markers of renal fibrosis.…”

“…Notable renoprotective effects were also observed in a rat unilateral ureteral obstruction renal fibrosis model, wherein treatment with praliciguat for 14 days following ureteral obstruction resulted in reductions in markers of renal fibrosis. In addition, praliciguat treatment in a lipopolysaccharide‐induced inflammation study in mice demonstrated significant reductions in the pro‐inflammatory cytokines IL‐6 and TNF‐α 7 . Clinically, oral administration of praliciguat in healthy volunteers was associated with elevation of cGMP and modest reductions in blood pressure, indicating target engagement and stimulation of the NO‐sGC‐cGMP pathway 8 .…”