Vericiguat (BAY1021189)
(Synonyms: 维利西呱; BAY1021189) 目录号 : GC32472
A stimulator of soluble guanylyl cyclase
Cas No.:1350653-20-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
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Animal experiment: | Rats: Rat are randomly allocated to three study groups: placebo (control), 24 low dose, and 24 high dose (3 and 10 mg/kg per day, respectively, administered po by gavage qd). Blood pressure is measured via the tail-cuff method once before the start of the study (day 0) to exclude preexisting differences between the groups and on day 7, 14, and 21. Body weight and survival are assessed on day 1, 8, and 15 and at the study end. At the end of the study (day 22), all animals are anesthetized, blood is collected, and animals are sacrificed; blood is taken in order to assess plasma parameters, and the heart is dissected into the left and right ventricles and is weighed to assess potential heart hypertrophy. Creatinine, urea, and renin activity in plasma are determined after extraction[1]. |
References: [1]. Follmann M, et al. Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure. J Med Chem. 2017 Jun 22;60(12):5146-5161. | |
Vericiguat is a stimulator of soluble guanylyl cyclase (sGC).1 It stimulates the formation of cGMP in CHO cells expressing recombinant rat sGC in the absence and presence of the nitric oxide (NO) donor SNAP , an effect that can be reversed by the sGC inhibitor ODQ . Vericiguat inhibits phenylephrine-induced contractions in isolated rabbit saphenous artery rings, rabbit aortic rings, and canine femoral vein rings (IC50s = 798, 692, and 3,072 nM, respectively), as well as decreases the coronary perfusion pressure in isolated perfused rat hearts in a concentration-dependent manner. It decreases proteinuria and increases survival in rats expressing mouse renin ((mRenR2)27), a transgenic model for hypertension, when administered at doses of 3 or 10 mg/kg. Formulations containing vericiguat have been used in the treatment of heart failure.
1.Follmann, M., Ackerstaff, J., Redlich, G., et al.Discovery of the soluble guanylate cyclase stimulator vericiguat (BAY 1021189) for the treatment of chronic heart failureJ. Med. Chem.60(12)5146-5161(2017)
| Cas No. | 1350653-20-1 | SDF | |
| 别名 | 维利西呱; BAY1021189 | ||
| Canonical SMILES | O=C(OC)NC1=C(N)N=C(C2=NN(CC3=CC=CC=C3F)C4=NC=C(F)C=C42)N=C1N | ||
| 分子式 | C19H16F2N8O2 | 分子量 | 426.38 |
| 溶解度 | DMSO : 60 mg/mL (140.72 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3453 mL | 11.7266 mL | 23.4533 mL |
| 5 mM | 0.4691 mL | 2.3453 mL | 4.6907 mL |
| 10 mM | 0.2345 mL | 1.1727 mL | 2.3453 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction
N Engl J Med 2020 May 14;382(20):1883-1893.PMID:32222134DOI:10.1056/NEJMoa1915928.
Background: The effect of Vericiguat, a novel oral soluble guanylate cyclase stimulator, in patients with heart failure and reduced ejection fraction who had recently been hospitalized or had received intravenous diuretic therapy is unclear. Methods: In this phase 3, randomized, double-blind, placebo-controlled trial, we assigned 5050 patients with chronic heart failure (New York Heart Association class II, III, or IV) and an ejection fraction of less than 45% to receive Vericiguat (target dose, 10 mg once daily) or placebo, in addition to guideline-based medical therapy. The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure. Results: Over a median of 10.8 months, a primary-outcome event occurred in 897 of 2526 patients (35.5%) in the Vericiguat group and in 972 of 2524 patients (38.5%) in the placebo group (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P = 0.02). A total of 691 patients (27.4%) in the Vericiguat group and 747 patients (29.6%) in the placebo group were hospitalized for heart failure (hazard ratio, 0.90; 95% CI, 0.81 to 1.00). Death from cardiovascular causes occurred in 414 patients (16.4%) in the Vericiguat group and in 441 patients (17.5%) in the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06). The composite of death from any cause or hospitalization for heart failure occurred in 957 patients (37.9%) in the Vericiguat group and in 1032 patients (40.9%) in the placebo group (hazard ratio, 0.90; 95% CI, 0.83 to 0.98; P = 0.02). Symptomatic hypotension occurred in 9.1% of the patients in the Vericiguat group and in 7.9% of the patients in the placebo group (P = 0.12), and syncope occurred in 4.0% of the patients in the Vericiguat group and in 3.5% of the patients in the placebo group (P = 0.30). Conclusions: Among patients with high-risk heart failure, the incidence of death from cardiovascular causes or hospitalization for heart failure was lower among those who received Vericiguat than among those who received placebo. (Funded by Merck Sharp & Dohme [a subsidiary of Merck] and Bayer; VICTORIA ClinicalTrials.gov number, NCT02861534.).
Vericiguat: First Approval
Drugs 2021 Apr;81(6):721-726.PMID:33770393DOI:10.1007/s40265-021-01496-z.
Vericiguat (VERQUVO™; Merck & Co, Bayer AG) is a soluble guanylate cyclase (sGC) stimulator being developed for the treatment of chronic heart failure. Vericiguat stimulates sGC and cGMP production independent of nitric oxide (NO) and enhances the effects of NO by stabilizing the NO-sGC binding. Based on the results of the phase III VICTORIA trial Vericiguat was recently approved in the USA for risk reduction in patients with heart failure and ejection fraction < 45%. This article summarizes the milestones in the development of Vericiguat leading to this first approval.
Clinical Outcomes and Response to Vericiguat According to Index Heart Failure Event: Insights From the VICTORIA Trial
JAMA Cardiol 2021 Jun 1;6(6):706-712.PMID:33185650DOI:10.1001/jamacardio.2020.6455.
Importance: The period following heart failure hospitalization (HFH) is a vulnerable time with high rates of death or recurrent HFH. Objective: To evaluate clinical characteristics, outcomes, and treatment response to Vericiguat according to prespecified index event subgroups and time from index HFH in the Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial. Design, setting, and participants: Analysis of an international, randomized, placebo-controlled trial. All VICTORIA patients had recent (<6 months) worsening HF (ejection fraction <45%). Index event subgroups were less than 3 months after HFH (n = 3378), 3 to 6 months after HFH (n = 871), and those requiring outpatient intravenous diuretic therapy only for worsening HF (without HFH) in the previous 3 months (n = 801). Data were analyzed between May 2, 2020, and May 9, 2020. Intervention: Vericiguat titrated to 10 mg daily vs placebo. Main outcomes and measures: The primary outcome was time to a composite of HFH or cardiovascular death; secondary outcomes were time to HFH, cardiovascular death, a composite of all-cause mortality or HFH, all-cause death, and total HFH. Results: Among 5050 patients in the VICTORIA trial, mean age was 67 years, 24% were women, 64% were White, 22% were Asian, and 5% were Black. Baseline characteristics were balanced between treatment arms within each subgroup. Over a median follow-up of 10.8 months, the primary event rates were 40.9, 29.6, and 23.4 events per 100 patient-years in the HFH at less than 3 months, HFH 3 to 6 months, and outpatient worsening subgroups, respectively. Compared with the outpatient worsening subgroup, the multivariable-adjusted relative risk of the primary outcome was higher in HFH less than 3 months (adjusted hazard ratio, 1.48; 95% CI, 1.27-1.73), with a time-dependent gradient of risk demonstrating that patients closest to their index HFH had the highest risk. Vericiguat was associated with reduced risk of the primary outcome overall and in all subgroups, without evidence of treatment heterogeneity. Similar results were evident for all-cause death and HFH. Addtionally, a continuous association between time from HFH and Vericiguat treatment showed a trend toward greater benefit with longer duration since HFH. Safety events (symptomatic hypotension and syncope) were infrequent in all subgroups, with no difference between treatment arms. Conclusions and relevance: Among patients with worsening chronic HF, those in closest proximity to their index HFH had the highest risk of cardiovascular death or HFH, irrespective of age or clinical risk factors. The benefit of Vericiguat did not differ significantly across the spectrum of risk in worsening HF. Trial registration: ClinicalTrials.gov Identifier: NCT02861534.
Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis
Cardiovasc Drugs Ther 2021 Oct;35(5):1067-1076.PMID:33074526DOI:10.1007/s10557-020-07099-2.
Background: Sacubitril/valsartan, Vericiguat, and the sodium-glucose co-transporter-2 inhibitors (SGLT2i) dapagliflozin and empagliflozin proved effective in phase 3 trials on heart failure with reduced ejection fraction (HFrEF). Methods: We compared the treatment arms (sacubitril/valsartan, Vericiguat, and SGLT2i) with the respective control arms (standard-of-care [SOC]) through a network meta-analysis of the phase 3 trials (PARADIGM-HF, VICTORIA, DAPA-HF, EMPEROR-Reduced), a phase 2 trial on Vericiguat and the HFrEF subgroup of DECLARE-TIMI 58. Results: There was a trend towards decreased risk of cardiovascular (CV) death or HF hospitalization with SGLT2i than sacubitril/valsartan (HR 0.92, 95% CI 0.81 to 1.05) and Vericiguat (HR 0.83, 95% CI 0.73 to 0.94). A non-significant effect of SGLT2i on CV mortality compared to sacubitril/valsartan (HR 1.04, 95% CI 0.88 to 1.24) and Vericiguat (HR 0.88, 95% CI 0.63 to 1.22) was found. SGLT2i demonstrated the greatest effect on HF hospitalization (HR 0.69, 95% CI 0.62 to 0.77) over the SOC, as well as a significant benefit over Vericiguat (HR 0.77, 95% CI 0.66 to 0.89), but not over sacubitril/valsartan (HR 0.87, 95% CI 0.75 to 1.02). SGLT2i were ranked as the most effective therapy, followed by sacubitril/valsartan and Vericiguat. Conclusions: Based on an indirect comparison, SGLT2i therapy is not associated with a significantly lower risk of CV death or HF hospitalization or CV death alone compared to sacubitril/valsartan or Vericiguat. The risk of HF hospitalization does not differ significantly between patients on SGLT2i or sacubitril/valsartan, while dapagliflozin is superior to Vericiguat. Registration number: PROSPERO ID 186351.
Effect of Vericiguat vs Placebo on Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The VITALITY-HFpEF Randomized Clinical Trial
JAMA 2020 Oct 20;324(15):1512-1521.PMID:33079152DOI:10.1001/jama.2020.15922.
Importance: Patients with heart failure and preserved ejection fraction (HFpEF) are at high risk of mortality, hospitalizations, and reduced functional capacity and quality of life. Objective: To assess the efficacy of the oral soluble guanylate cyclase stimulator Vericiguat on the physical limitation score (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ). Design, setting, and participants: Phase 2b randomized, double-blind, placebo-controlled, multicenter trial of 789 patients with chronic HFpEF and left ventricular ejection fraction 45% or higher with New York Heart Association class II-III symptoms, within 6 months of a recent decompensation (HF hospitalization or intravenous diuretics for HF without hospitalization), and with elevated natriuretic peptides, enrolled at 167 sites in 21 countries from June 15, 2018, through March 27, 2019; follow-up was completed on November 4, 2019. Interventions: Patients were randomized to receive Vericiguat, up-titrated to 15-mg (n = 264) or 10-mg (n = 263) daily oral dosages, compared with placebo (n = 262) and randomized 1:1:1. Main outcomes and measures: The primary outcome was change in the KCCQ PLS (range, 0-100; higher values indicate better functioning) after 24 weeks of treatment. The secondary outcome was 6-minute walking distance from baseline to 24 weeks. Results: Among 789 randomized patients, the mean age was 72.7 (SD, 9.4) years; 385 (49%) were female; mean EF was 56%; and median N-terminal pro-brain natriuretic peptide level was 1403 pg/mL; 761 (96.5%) completed the trial. The baseline and 24-week KCCQ PLS means for the 15-mg/d Vericiguat, 10-mg/d Vericiguat, and placebo groups were 60.0 and 68.3, 57.3 and 69.0, and 59.0 and 67.1, respectively, and the least-squares mean changes were 5.5, 6.4, and 6.9, respectively. The least-squares mean difference in scores between the 15-mg/d Vericiguat and placebo groups was -1.5 (95% CI, -5.5 to 2.5; P = .47) and between the 10-mg/d Vericiguat and placebo groups was -0.5 (95% CI, -4.6 to 3.5; P = .80). The baseline and 24-week 6-minute walking distance mean scores in the 15-mg/d Vericiguat, 10-mg/d Vericiguat, and placebo groups were 295.0 m and 311.8m , 292.1 m and 318.3 m, and 295.8 m and 311.4 m, and the least-squares mean changes were 5.0 m, 8.7 m, and 10.5 m, respectively. The least-squares mean difference between the 15-mg/d Vericiguat and placebo groups was -5.5 m (95% CI, -19.7 m to 8.8 m; P = .45) and between the 10-mg/d Vericiguat and placebo groups was -1.8 m (95% CI, -16.2 m to 12.6 m; P = .81), respectively. The proportions of patients who experienced symptomatic hypotension were 6.4% in the 15-mg/d Vericiguat group, 4.2% in the 10-mg/d Vericiguat group, and 3.4% in the placebo group; those with syncope were 1.5%, 0.8%, and 0.4%, respectively. Conclusions and relevance: Among patients with HFpEF and recent decompensation, 24-week treatment with Vericiguat at either 15-mg/d or 10-mg/d dosages compared with placebo did not improve the physical limitation score of the KCCQ. Trial registration: ClinicalTrials.gov Identifier: NCT03547583.