PMID- 29643251 OWN - NLM STAT- MEDLINE DCOM- 20191014 LR - 20200520 IS - 1521-0103 (Electronic) IS - 0022-3565 (Linking) VI - 365 IP - 3 DP - 2018 Jun 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. PG - 664-675 LID - 10.1124/jpet.117.247429 [doi] 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. CI - Copyright (c) 2018 The Author(s). FAU - Tobin, Jenny V AU - Tobin JV AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts jtobin@ironwoodpharma.com. FAU - Zimmer, Daniel P AU - Zimmer DP AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Shea, Courtney AU - Shea C AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Germano, Peter AU - Germano P AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Bernier, Sylvie G AU - Bernier SG AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Liu, Guang AU - Liu G AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Long, Kim AU - Long K AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Miyashiro, Joy AU - Miyashiro J AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Ranganath, Sheila AU - Ranganath S AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Jacobson, Sarah AU - Jacobson S AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Tang, Kim AU - Tang K AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Im, G-Yoon Jamie AU - Im GJ AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Sheppeck, James 2nd AU - Sheppeck J 2nd AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Moore, Joel D AU - Moore JD AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Sykes, Kristine AU - Sykes K AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Wakefield, James AU - Wakefield J AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Sarno, Renee AU - Sarno R AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Banijamali, Ali R AU - Banijamali AR AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Profy, Albert T AU - Profy AT AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Milne, G Todd AU - Milne GT AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Currie, Mark G AU - Currie MG AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. FAU - Masferrer, Jaime L AU - Masferrer JL AD - Ironwood Pharmaceuticals, Cambridge, Massachusetts. LA - eng PT - Journal Article DEP - 20180411 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Antihypertensive Agents) RN - 0 (Pyrazoles) RN - 0 (Pyrimidines) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 4.6.1.2 (Soluble Guanylyl Cyclase) RN - R1S0H458SA (praliciguat) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*pharmacokinetics/*pharmacology/therapeutic use MH - Antihypertensive Agents/*pharmacokinetics/*pharmacology/therapeutic use MH - Arteries/drug effects/physiology MH - Blood Pressure/drug effects MH - Disease Models, Animal MH - Endothelium, Vascular/drug effects/metabolism MH - Fibrosis MH - HEK293 Cells MH - Humans MH - Kidney/drug effects/pathology MH - Male MH - Mice MH - Nitric Oxide/metabolism MH - Proteinuria/drug therapy MH - Pyrazoles/*pharmacokinetics/*pharmacology/therapeutic use MH - Pyrimidines/*pharmacokinetics/*pharmacology/therapeutic use MH - Rats MH - Signal Transduction/drug effects MH - Soluble Guanylyl Cyclase/*metabolism MH - Tissue Distribution MH - Vasodilation/drug effects EDAT- 2018/04/13 06:00 MHDA- 2019/10/15 06:00 CRDT- 2018/04/13 06:00 PHST- 2017/12/21 00:00 [received] PHST- 2018/03/20 00:00 [accepted] PHST- 2018/04/13 06:00 [pubmed] PHST- 2019/10/15 06:00 [medline] PHST- 2018/04/13 06:00 [entrez] AID - jpet.117.247429 [pii] AID - 10.1124/jpet.117.247429 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2018 Jun;365(3):664-675. doi: 10.1124/jpet.117.247429. Epub 2018 Apr 11.