RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 664
OP 675
DO 10.1124/jpet.117.247429
VO 365
IS 3
A1 Jenny V. Tobin
A1 Daniel P. Zimmer
A1 Courtney Shea
A1 Peter Germano
A1 Sylvie G. Bernier
A1 Guang Liu
A1 Kim Long
A1 Joy Miyashiro
A1 Sheila Ranganath
A1 Sarah Jacobson
A1 Kim Tang
A1 G-Yoon Jamie Im
A1 James Sheppeck II
A1 Joel D. Moore
A1 Kristine Sykes
A1 James Wakefield
A1 Renee Sarno
A1 Ali R. Banijamali
A1 Albert T. Profy
A1 G. Todd Milne
A1 Mark G. Currie
A1 Jaime L. Masferrer
YR 2018
UL http://jpet.aspetjournals.org/content/365/3/664.abstract
AB 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.