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PHARMACOLOGICAL CHARACTERIZATION OF IW-1973, A NOVEL SOLUBLE GUANYLATE CYCLASE STIMULATOR WITH EXTENSIVE TISSUE DISTRIBUTION, ANTI-HYPERTENSIVE, ANTI-INFLAMMATORY, AND ANTI-FIBROTIC EFFECTS IN PRECLINICAL MODELS OF DISEASE.

PHARMACOLOGICAL CHARACTERIZATION OF IW-1973, A NOVEL SOLUBLE GUANYLATE CYCLASE STIMULATOR WITH EXTENSIVE TISSUE DISTRIBUTION, ANTI-HYPERTENSIVE, ANTI-INFLAMMATORY, AND ANTI-FIBROTIC EFFECTS IN PRECLINICAL MODELS OF DISEASE.
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Tobin JV, Zimmer DP, Shea C, Germano P, Bernier SG, Liu G, Long K, Miyashiro J, Ranganath S, Jacobson S, Tang K, Im GJ, Sheppeck J, Moore JD, Sykes K, Wakefield J, Sarno R, Banijamali AR, Profy AT, Milne GT, Currie MG, Masferrer JL,


Tobin JV, Zimmer DP, Shea C, Germano P, Bernier SG, Liu G, Long K, Miyashiro J, Ranganath S, Jacobson S, Tang K, Im GJ, Sheppeck J, Moore JD, Sykes K, Wakefield J, Sarno R, Banijamali AR, Profy AT, Milne GT, Currie MG, Masferrer JL, (click to view)

Tobin JV, Zimmer DP, Shea C, Germano P, Bernier SG, Liu G, Long K, Miyashiro J, Ranganath S, Jacobson S, Tang K, Im GJ, Sheppeck J, Moore JD, Sykes K, Wakefield J, Sarno R, Banijamali AR, Profy AT, Milne GT, Currie MG, Masferrer JL,

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The Journal of pharmacology and experimental therapeutics 2018 04 11() pii jpet.117.247429
Abstract

Soluble guanylate cyclase (sGC), a key signal-transduction enzyme, increases the conversion of guanosine-5′-triphosphate (GTP) to cyclic guanosine-3′,5′-monophosphate (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. sGC stimulators are small-molecule drugs that bind sGC and enhance NO-mediated cGMP signaling. The pharmacological characterization of IW-1973, a novel clinical-stage sGC stimulator, 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 (VASP). 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, results that were affirmed in mouse LPS-induced inflammation and rat unilateral ureteral obstruction renal fibrosis models. A quantitative whole-body autoradiography study of IW-1973 revealed extensive tissue distribution. 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 exhibited renoprotective, anti-inflammatory, and antifibrotic effects in nonclinical models. IW-1973 is currently under clinical investigation for treatment of heart failure with preserved ejection fraction and microvascular complications of diabetes including diabetic nephropathy.

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