PT  - JOURNAL ARTICLE
AU  - Jenny V. Tobin
AU  - Daniel P. Zimmer
AU  - Courtney Shea
AU  - Peter Germano
AU  - Sylvie G. Bernier
AU  - Guang Liu
AU  - Kim Long
AU  - Joy Miyashiro
AU  - Sheila Ranganath
AU  - Sarah Jacobson
AU  - Kim Tang
AU  - G-Yoon Jamie Im
AU  - James Sheppeck II
AU  - Joel D. Moore
AU  - Kristine Sykes
AU  - James Wakefield
AU  - Renee Sarno
AU  - Ali R. Banijamali
AU  - Albert T. Profy
AU  - G. Todd Milne
AU  - Mark G. Currie
AU  - Jaime L. Masferrer
TI  - 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
AID  - 10.1124/jpet.117.247429
DP  - 2018 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 664--675
VI  - 365
IP  - 3
4099  - http://jpet.aspetjournals.org/content/365/3/664.short
4100  - http://jpet.aspetjournals.org/content/365/3/664.full
SO  - J Pharmacol Exp Ther2018 Jun 01; 365
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.