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Praliciguat Sale

(Synonyms: IW-1973) 目录号 : GC65449

Praliciguat (IW-1973) 是一种有效、可口服的可溶性鸟甘酸环化酶 (soluble guanylate cyclase) 促进剂,增强 NO 信号通路,为血管舒张剂。在 HEK-293 细胞中,Praliciguat (IW-1973) 能够刺激 sGC,EC50 值为 197 nM。

Praliciguat Chemical Structure

Cas No.:1628730-49-3

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10mM (in 1mL DMSO)
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5mg
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产品描述

Praliciguat (IW-1973) is a potent and orally active soluble guanylate cyclase stimulator, enhances NO signaling, acts as a vasodilator. Praliciguat (IW-1973) stimulates sGC in HEK-293 cells with an EC50 of 197 nM[1].

[1]. Daniel P Zimmer, et al. Abstract 16938: IW-1973 is a Potent Soluble Guanylate Cyclase Stimulator in vitro and in vivo With Extensive Tissue Distribution.

Chemical Properties

Cas No. 1628730-49-3 SDF Download SDF
别名 IW-1973
分子式 C21H14F8N6O2 分子量 534.36
溶解度 DMSO : 250 mg/mL (467.85 mM; Need ultrasonic) 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 1.8714 mL 9.357 mL 18.714 mL
5 mM 0.3743 mL 1.8714 mL 3.7428 mL
10 mM 0.1871 mL 0.9357 mL 1.8714 mL
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Research Update

Praliciguat Promotes Ischemic Leg Reperfusion in Leptin Receptor-Deficient Mice

Circ Res 2023 Jan 6;132(1):34-48.PMID:36448444DOI:10.1161/CIRCRESAHA.122.322033.

Background: Lower-limb peripheral artery disease is one of the major complications of diabetes. Peripheral artery disease is associated with poor limb and cardiovascular prognoses, along with a dramatic decrease in life expectancy. Despite major medical advances in the treatment of diabetes, a substantial therapeutic gap remains in the peripheral artery disease population. Praliciguat is an orally available sGC (soluble guanylate cyclase) stimulator that has been reported both preclinically and in early stage clinical trials to have favorable effects in metabolic and hemodynamic outcomes, suggesting that it may have a potential beneficial effect in peripheral artery disease. Methods: We evaluated the effect of Praliciguat on hind limb ischemia recovery in a mouse model of type 2 diabetes. Hind limb ischemia was induced in leptin receptor-deficient (Leprdb/db) mice by ligation and excision of the left femoral artery. Praliciguat (10 mg/kg/day) was administered in the diet starting 3 days before surgery. Results: Twenty-eight days after surgery, ischemic foot perfusion and function parameters were better in praliciguat-treated mice than in vehicle controls. Improved ischemic foot perfusion was not associated with either improved traditional cardiovascular risk factors (ie, weight, glycemia) or increased angiogenesis. However, treatment with Praliciguat significantly increased arteriole diameter, decreased ICAM1 (intercellular adhesion molecule 1) expression, and prevented the accumulation of oxidative proangiogenic and proinflammatory muscle fibers. While investigating the mechanism underlying the beneficial effects of Praliciguat therapy, we found that Praliciguat significantly downregulated Myh2 and Cxcl12 mRNA expression in cultured myoblasts and that conditioned medium form praliciguat-treated myoblast decreased ICAM1 mRNA expression in endothelial cells. These results suggest that Praliciguat therapy may decrease ICAM1 expression in endothelial cells by downregulating Cxcl12 in myocytes. Conclusions: Our results demonstrated that Praliciguat promotes blood flow recovery in the ischemic muscle of mice with type 2 diabetes, at least in part by increasing arteriole diameter and by downregulating ICAM1 expression.

Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model

Front Pharmacol 2022 Mar 4;13:852080.PMID:35308230DOI:10.3389/fphar.2022.852080.

Praliciguat is a soluble guanylate cyclase stimulator that elicits hemodynamic, anti-inflammatory, and antifibrotic effects in preclinical models of metabolic dysfunction. We assessed the metabolic effects of Praliciguat in a mouse diet-induced obesity (DIO) model housed at thermoneutrality. At 6 weeks old, male C57BL/6N mice were either maintained on low-fat diet (LFD, lean mice) or placed on 60% high-fat diet (HFD, DIO mice). At 14 weeks old, the DIO mice were either maintained on HFD or switched to HFD with Praliciguat (6-mg/kg). Day 28 samples were collected for biomarker analysis. In a second study under the same paradigm, indirect calorimetry was performed on days 8, 9, 20, 21, 32, and 33 and an oral lipid tolerance test (LTT) on day 38. Mice treated 28 days with Praliciguat had lower levels of fasting plasma insulin, C-peptide, triglycerides, and HOMA-IR (homeostatic model assessment for insulin resistance) than DIO controls. In addition, energy expenditure was higher in praliciguat-treated than in DIO control mice on days 9, 20, 32, and 33; and day-38 triglycerides were lower. HFD-induced increases in gene expression of liver TNF-ɑ, lipoprotein lipase (Lpl), and patatin-like phospholipase domain-containing protein 3 (Pnpla3) in control DIO mice were attenuated in praliciguat-treated DIO mice. The positive metabolic effects observed in praliciguat-treated mice were associated with the restoration of liver PI3K (pAKT-Thr308) signaling, but not MAPK (pERK). In conclusion, praliciguat-treated DIO mice had increased energy utilization, improved insulin sensitivity, and lower plasma triglycerides. These results illustrate metabolic effects associated with Praliciguat treatment in DIO mice.

Praliciguat inhibits progression of diabetic nephropathy in ZSF1 rats and suppresses inflammation and apoptosis in human renal proximal tubular cells

Am J Physiol Renal Physiol 2020 Oct 1;319(4):F697-F711.PMID:32865013DOI:10.1152/ajprenal.00003.2020.

Praliciguat, a clinical-stage soluble guanylate cyclase (sGC) stimulator, increases cGMP via the nitric oxide-sGC pathway. Praliciguat has been shown to be renoprotective in rodent models of hypertensive nephropathy and renal fibrosis. In the present study, Praliciguat alone and in combination with enalapril attenuated proteinuria in the obese ZSF1 rat model of diabetic nephropathy. Praliciguat monotherapy did not affect hemodynamics. In contrast, enalapril monotherapy lowered blood pressure but did not attenuate proteinuria. Renal expression of genes in pathways involved in inflammation, fibrosis, oxidative stress, and kidney injury was lower in praliciguat-treated obese ZSF1 rats than in obese control rats; fasting glucose and cholesterol were also lower with Praliciguat treatment. To gain insight into how tubular mechanisms might contribute to its pharmacological effects on the kidneys, we studied the effects of Praliciguat on pathological processes and signaling pathways in cultured human primary renal proximal tubular epithelial cells (RPTCs). Praliciguat inhibited the expression of proinflammatory cytokines and secretion of monocyte chemoattractant protein-1 in tumor necrosis factor-α-challenged RPTCs. Praliciguat treatment also attenuated transforming growth factor-β-mediated apoptosis, changes to a mesenchyme-like cellular phenotype, and phosphorylation of SMAD3 in RPTCs. In conclusion, Praliciguat improved proteinuria in the ZSF1 rat model of diabetic nephropathy, and its actions in human RPTCs suggest that tubular effects may contribute to its renal benefits, building upon strong evidence for the role of cGMP signaling in renal health.

Novel Therapies for Kidney Disease in People With Diabetes

J Clin Endocrinol Metab 2022 Jan 1;107(1):e1-e24.PMID:34460928DOI:10.1210/clinem/dgab639.

Context: The increasing burden of diabetic kidney disease (DKD) has led to the discovery of novel therapies. Objective: This review aims to summarize the results of recent clinical trials that test the efficacy of potential therapies for DKD. Methods: A systematized narrative review was performed utilizing the PubMed, Embase (Ovid), CINAHL, and Cochrane databases (January 2010 to January 2021). The included trials assessed the efficacy of specific medications using renal endpoints in adult participants with type 1 or 2 diabetes. Results: Fifty-three trials were identified. Large, multinational, and high-powered trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrated improved renal outcomes, even in patients with established DKD. Trials examining incretin-related therapies also showed some improvement in renal outcomes. Additionally, mineralocorticoid receptor antagonists exhibited potential with multiple improved renal outcomes in large trials, including those involving participants with established DKD. Atrasentan, baricitinib, ASP8232, PF-04634817, CCX140-B, atorvastatin, fenofibrate, probucol, doxycycline, vitamin D, omega-3 fatty acids, silymarin, turmeric, total glucosides of paeony, and tripterygium wilfordii Hook F extract were all associated with some improved renal endpoints but need further exploration. While bardoxolone methyl was associated with a decrease in albuminuria, high rates of cardiovascular adverse effects curtailed further exploration into this agent. Selonsertib, allopurinol, Praliciguat, palosuran, benfotiamine, and diacerein were not associated with improved renal outcomes. Conclusion: Trials have yielded promising results in the search for new therapies to manage DKD. SGLT2 inhibitors and incretin-related therapies have demonstrated benefit and were associated with improved cardiovascular outcomes. Mineralocorticoid receptor antagonists are another class of agents with increasing evidence of benefits.

Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: The CAPACITY HFpEF Randomized Clinical Trial

JAMA 2020 Oct 20;324(15):1522-1531.PMID:33079154DOI:10.1001/jama.2020.16641.

Importance: Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency. Objective: To evaluate the efficacy and adverse effects of Praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF. Design, setting, and participants: CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 Praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg Praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019. Interventions: Patients were randomized to receive 12 weeks of treatment with 40 mg of Praliciguat daily (n = 91) or placebo (n = 90). Main outcomes and measures: The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs). Results: Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and Praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min ([95% CI, -0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and Praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and Praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with Praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the Praliciguat group and 11% in the placebo group). Conclusions and relevance: Among patients with HFpEF, the soluble guanylate cyclase stimulator Praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of Praliciguat in patients with HFpEF. Trial registration: ClinicalTrials.gov Identifier: NCT03254485.