Ensifentrine
(Synonyms: RPL-554) 目录号 : GC62466
Ensifentrine (RPL-554) 是一种吸入式，首创的磷酸二酯酶 3 (PDE3) 和 PDE4 双重抑制剂，IC50 分别为 0.4 nM 和 1479 nM。Ensifentrine 具有支气管保护和抗炎活性，可用于慢性阻塞性肺疾病 (COPD) 的研究。
Cas No.:1884461-72-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Ensifentrine (RPL-554) is an inhaled first-in-class dual inhibitor of phosphodiesterase 3 (PDE3) and PDE4 with IC50s of 0.4 nM and 1479 nM, respectively. Ensifentrine has bronchoprotective and anti-inflammatory activities. Ensifentrine can be used for chronic obstructive pulmonary disease (COPD) research[1][2].
Ensifentrine (RPL-554) inhibits, in a concentration-dependent manner, lipopolysaccharide-induced TNF-α release from human monocytes (IC50 of 0.52 μM) and proliferation of human mononuclear cells to phytohemagglutinin (IC50 of 0.46 μM)[1]. Electrical field stimulation-induced contraction of guinea pig superfused isolated tracheal preparations is significantly inhibited by Ensifentrine (10 μM). Contractile responses are suppressed for up to 12 h after termination of superfusion with RPL-554 demonstrating a long duration of action[1].
Ensifentrine (RPL-554; 10 mg/kg; Oral administration; once) significantly inhibits eosinophil recruitment following antigen challenge in ovalbumin-sensitized guinea pigs[1]. The inhalation of dry powder containing Ensifentrine by conscious guinea pigs (25% in micronized lactose) 1.5 h before antigen exposure significantly inhibits the recruitment of eosinophils to the airways[1]. Exposure of conscious guinea pigs to inhalation of dry powder containing Ensifentrine (2.5%) in micronized lactose significantly inhibits histamine-induced plasma protein extravasation in the trachea and histamine-induced bronchoconstriction over a 5.5-h period[1].
[1]. Victoria Boswell-Smith, et al. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]. J Pharmacol Exp Ther. 2006 Aug;318(2):840-8.
[2]. Henrik Watz, et al. Symptom Improvement Following Treatment with the Inhaled Dual Phosphodiesterase 3 and 4 Inhibitor Ensifentrine in Patients with Moderate to Severe COPD - A Detailed Analysis. Int J Chron Obstruct Pulmon Dis. 2020 Sep 16;15:2199-2206.
| Cas No. | 1884461-72-6 | SDF | |
| 别名 | RPL-554 | ||
| 分子式 | C26H31N5O4 | 分子量 | 477.56 |
| 溶解度 | DMSO : 25 mg/mL (52.35 mM; Need ultrasonic) | 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 | 2.094 mL | 10.4699 mL | 20.9398 mL |
| 5 mM | 0.4188 mL | 2.094 mL | 4.188 mL |
| 10 mM | 0.2094 mL | 1.047 mL | 2.094 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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工作液浓度： mg/ml；
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2.
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Ensifentrine (RPL554): an investigational PDE3/4 inhibitor for the treatment of COPD
Expert Opin Investig Drugs 2019 Oct;28(10):827-833.PMID:31474120DOI:10.1080/13543784.2019.1661990.
Introduction: A compound that simultaneously inhibits PDE3 and PDE4 should increase airway caliber by relaxing the smooth muscle and, simultaneously, suppress airway inflammatory responses. Ensifentrine (RPL554) is considered a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4, that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis. Areas covered: We analyze the development of this molecule from its basic pharmacology to the present clinical Phase II studies. Expert opinion: Ensifentrine is an interesting drug but there is a lack of solid studies that still does not allow us to correctly allocate this molecule in the current COPD and even asthma therapeutic armamentarium. Furthermore, apparently Ensifentrine has not yet entered Phase III clinical development and, in any case, there is no reliable evidence of its ability to elicit an anti-inflammatory activity in patients with COPD or asthma. Therefore, the real anti-inflammatory profile of Ensifentrine must be clarified with new studies of basic pharmacology and adequate clinical studies specifically designed. However, at present the most intriguing perspective is linked to its possible use in the treatment of cystic fibrosis, also considering the lack of valid therapeutic options for this disease.
The Phosphodiesterase Inhibitor Ensifentrine Reduces Production of Proinflammatory Mediators in Well Differentiated Bronchial Epithelial Cells by Inhibiting PDE4
J Pharmacol Exp Ther 2020 Dec;375(3):414-429.PMID:33012706DOI:10.1124/jpet.120.000080.
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel that impair airway salt and fluid secretion. Excessive release of proinflammatory cytokines and chemokines by CF bronchial epithelium during airway infection leads to chronic inflammation and a slow decline in lung function; thus, there is much interest in finding safe and effective treatments that reduce inflammation in CF. We showed previously that the cyclic nucleotide phosphodiesterase (PDE) inhibitor Ensifentrine (RPL554; Verona Pharma) stimulates the channel function of CFTR mutants with abnormal gating and also those with defective trafficking that are partially rescued using a clinically approved corrector drug. PDE inhibitors also have known anti-inflammatory effects; therefore, we examined whether Ensifentrine alters the production of proinflammatory cytokines in CF bronchial epithelial cells. Ensifentrine reduced the production of monocyte chemoattractant protein-1 and granulocyte monocyte colony-stimulating factor (GM-CSF) during challenge with interleukin-1β Comparing the effect of Ensifentrine with milrinone and roflumilast, selective PDE3 and PDE4 inhibitors, respectively, demonstrated that the anti-inflammatory effect of Ensifentrine was mainly due to inhibition of PDE4. Beneficial modulation of GM-CSF was further enhanced when Ensifentrine was combined with low concentrations of the β 2-adrenergic agonist isoproterenol or the corticosteroid dexamethasone. The results indicate that Ensifentrine may have beneficial anti-inflammatory effects in CF airways particularly when used in combination with β 2-adrenergic agonists or corticosteroids. SIGNIFICANCE STATEMENT: Airway inflammation that is disproportionate to the burden of chronic airway infection causes much of the pathology in the cystic fibrosis (CF) lung. We show here that Ensifentrine beneficially modulates the release of proinflammatory factors in well differentiated CF bronchial epithelial cells that is further enhanced when combined with β2-adrenergic agonists or low-concentration corticosteroids. The results encourage further clinical testing of Ensifentrine, alone and in combination with β2-adrenergic agonists or low-concentration corticosteroids, as a novel anti-inflammatory therapy for CF.
Ensifentrine (RPL554): an inhaled 'bifunctional' dual PDE3/4 inhibitor for the treatment of asthma and chronic obstructive pulmonary disease
Pharm Pat Anal 2018 Nov;7(6):249-257.PMID:30657422DOI:10.4155/ppa-2018-0030.
Ensifentrine (RPL554), an inhaled 'bifunctional' dual phosphodiesterase 3/4 inhibitor that exhibits both bronchodilator and anti-inflammatory activities, provides a new option in the treatment of chronic obstructive pulmonary disease (COPD) and other inflammatory airway diseases that are under clinical development. Ensifentrine appears to be initially under development for the treatment of COPD although it is not yet clear whether it should be understood as an add-on therapy in patients for the treatment of acute exacerbations of COPD or for the regular maintenance treatment of patients either alone, or on top of existing drug classes.
A dose-ranging study of the inhaled dual phosphodiesterase 3 and 4 inhibitor Ensifentrine in COPD
Respir Res 2020 Feb 10;21(1):47.PMID:32041601DOI:10.1186/s12931-020-1307-4.
Background: Many patients with chronic obstructive pulmonary disease (COPD) still experience daily symptoms, exacerbations, and accelerated lung function decline, even when receiving maximal combined treatment with inhaled long-acting bronchodilators and corticosteroids. Novel treatment options are needed for these patients. Phosphodiesterases (PDEs) are enzymes that impact a range of cellular functions by modulating levels of cyclic nucleotides, and there is evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive (or perhaps synergistic) effects. This study investigated the efficacy and safety of Ensifentrine, a first-in-class dual inhibitor of PDE 3 and 4, in patients with COPD. Methods: This randomised, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 40-80% predicted and FEV1/forced vital capacity ratio ≤ 0.7. Patients were randomised equally to inhale nebulised Ensifentrine 0.75, 1.5, 3 or 6 mg or placebo, all twice daily. Primary outcome: placebo-adjusted difference in peak FEV1 (assessed over 3 h) at Week 4. Results: The study took place between July 2017 and February 2018. Of 405 patients randomly assigned to medication, 375 (92.6%) completed the study. For peak FEV1 at Week 4, all four Ensifentrine doses were superior to placebo (p ≤ 0.0001) with least squares mean differences of 146 (95% CI 75-216), 153 (83-222), 200 (131-270) and 139 (69-210) mL for Ensifentrine 0.75, 1.5, 3 and 6 mg, respectively. Respiratory symptoms (assessed using the Evaluating Respiratory Symptoms questionnaire) were also significantly improved with all Ensifentrine doses at Week 4. Adverse events were reported by 33.3, 44.4, 35.4 and 36.3% patients with Ensifentrine 0.75, 1.5, 3 and 6 mg, respectively, and 39.2% with placebo. Conclusions: In this four-week Phase IIb study, all four Ensifentrine doses significantly improved bronchodilation and symptoms, with a dose-ranging effect from 0.75 to 3 mg twice daily, and all doses well tolerated. The study supports the continuing development of Ensifentrine in COPD. Trial registration: EudraCT 2016-005205-40, registered 30 May 2017.
Efficacy and safety of a first-in-class inhaled PDE3/4 inhibitor (Ensifentrine) vs salbutamol in asthma
Pulm Pharmacol Ther 2019 Oct;58:101814.PMID:31202957DOI:10.1016/j.pupt.2019.101814.
Introduction: This study aimed to investigate the dose-response and pharmacology of a range of single doses of nebulised Ensifentrine (RPL554), an inhaled dual phosphodiesterase (PDE) 3/4 inhibitor in patients with asthma. Methods: In this randomised, placebo-controlled, double-blind crossover study, patients received single nebulised doses of Ensifentrine 0.4, 1.5, 6 and 24 mg, salbutamol 2.5 and 7.5 mg, and placebo. Eligible patients were adults with asthma, pre-bronchodilator forced expiratory volume in 1 s (FEV1) 60-90% predicted and ≥1.5 L, with post-salbutamol FEV1 increase ≥15%. The co-primary objectives were peak and average FEV1 over 12 h for Ensifentrine vs placebo and salbutamol. Secondary endpoints included: peak and average systolic and diastolic blood pressure, pulse rate and ECG heart rate; and safety and tolerability (adverse events [AEs], and serum potassium). ClinicalTrials.gov: NCT02427165. Results: A total of 29 patients were randomised, with 25 (89%) completing the study. For the two co-primary endpoints there was a clear Ensifentrine dose-response relationship, with all treatments superior to placebo (p < 0.001). There was no relationship between the Ensifentrine dose and AE incidence or blood pressure. Ensifentrine 0.4, 1.5 and 6 mg had significantly lower effects than both salbutamol doses on pulse and heart rates. Ensifentrine did not impact potassium, whereas there was a was a dose-related reduction for salbutamol. Inhalation of Ensifentrine resulted in a dose-related increase in plasma exposure. Conclusions: Single-dose Ensifentrine demonstrated dose-dependent bronchodilation, and was as effective as a therapeutic dose of nebulised salbutamol. All Ensifentrine doses were similarly well tolerated, and did not show the characteristic β2-agonist systemic adverse effects.