AZD8848
目录号 : GC62488
AZD8848 是一种选择性的 TLR7 前体药激动剂，用于哮喘和过敏性鼻炎的研究。
Cas No.:866269-28-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
AZD8848 is a selective toll-like receptor 7 (TLR7) antedrug agonist which is developed for the research of asthma and allergic rhinitis[1].
AZD8848 shows good activity against TLR7, with cellular pEC50s of 7.0 and 6.6 for human TLR7 and rat TLR7, respectively[1].AZD8848 has an EC50 of 4 nM in the induction of IFNα from human PBMCs and an IC50 of 0.2-1.0 nM for the inhibition of IL-5, irrespective of whether the T cells have been polyclonally stimulated with PHA or via antigen presentation[1].AZD8848 is a potent, selective TLR7 agonist antedrug able to inhibit Th2 responses in vitro[1].AZD8848 has no activity against human TLR8 or against any of the other human TLRs[1].
AZD8848 (0.1-1 mg/kg; intratracheal) has a good pharmacokinetics in the Brown Norway rat[1].AZD8848 (0.3 mg/kg; Intratracheal) suppresses the ovalbumin (OVA) challenge in the rat allergy model[1].
[1]. Delaney S, et al. Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848. BMJ Open Respir Res. 2016 Feb 23;3(1):e000113.
| Cas No. | 866269-28-5 | SDF | |
| 分子式 | C29H43N7O5 | 分子量 | 569.7 |
| 溶解度 | 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 | 1.7553 mL | 8.7765 mL | 17.5531 mL |
| 5 mM | 0.3511 mL | 1.7553 mL | 3.5106 mL |
| 10 mM | 0.1755 mL | 0.8777 mL | 1.7553 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。
Tolerability in man following inhalation dosing of the selective TLR7 agonist, AZD8848
BMJ Open Respir Res 2016 Feb 23;3(1):e000113.PMID:26933507DOI:10.1136/bmjresp-2015-000113.
Background: Many patients with asthma have a T-helper type 2 (Th2) driven inflammation of the lung, whereas toll-like receptor 7 (TLR7) agonists, by inducing type I interferons, inhibit Th2 responses. In man, oral or parenteral TLR7 agonists can induce influenza-like symptoms through systemic induction of type I interferons. Design of a TLR7 agonist that is only active in the lung could reduce the risk of side effects and offer a new means for treating asthma. We developed a TLR7 agonist antedrug, AZD8848, to determine its local and systemic effects in preclinical models and man. Methods: In vitro cellular potencies for the TLR7 antedrug agonist, AZD8848, were determined along with pharmacokinetics and efficacy in a rat allergy model. Sputum and blood biomarkers were measured in single ascending and multiple ascending dose clinical studies following inhalation delivery of AZD8848 and tolerability assessed. Results: AZD8848 was potent in cellular assays and pharmacokinetics confirmed lack of systemic exposure to AZD8848. Weekly lung dosing in an animal model showed efficacy 26 days beyond the final dose. In healthy volunteers, AZD8848 was initially well tolerated with target engagement being demonstrated by induction of CXCL10 in sputum. A second inhaled dose, given 1 week later, amplified the systemic interferon signal in more than half the participants and resulted in significant influenza-like symptoms. Conclusions: The antedrug design restricted the direct actions of AZD8848 to the lung. However, the type I interferon induced locally by TLR7 spilled over systemically, limiting the utility of this inhaled antedrug approach. Trial registration number: NCT01560234, NCT01818869.
Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis
Respir Res 2012 Jun 22;13(1):53.PMID:22726593DOI:10.1186/1465-9921-13-53.
Background: Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile. Objective: To evaluate the efficacy and safety of intranasal AZD8848. Methods: In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779). In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 μg) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003). Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. Results: AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30-100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848. Conclusions: Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis. Trial registration: NCT00688779 and NCT00770003 as indicated above.
Effects of the Toll-like receptor 7 (TLR7) agonist, AZD8848, on allergen-induced responses in patients with mild asthma: a double-blind, randomised, parallel-group study
Respir Res 2019 Dec 19;20(1):288.PMID:31856838DOI:10.1186/s12931-019-1252-2.
Background: Although allergic asthma is a complex area with many interacting factors involved, the 'hygiene hypothesis' proposes that a lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive Th2-type responses in genetically susceptible individuals. Toll-like receptors (TLRs) play a key role within the innate immune system and TLR7 agonists have previously been shown to up-regulate Th1 responses and down-regulate Th2 responses to allergens in murine models of allergic or chronic asthma. This study aimed to examine the efficacy and safety of the novel TRL7 agonist AZD8848, which has been developed as an antedrug. Methods: In this double-blind, randomised, parallel-group study, AZD8848 60 μg or placebo was administered intranasally once-weekly for 8 weeks in patients with mild-to-moderate allergic asthma (NCT00999466). Efficacy assessments were performed at 1 and 4 weeks after the last dose. The primary outcome was the late asthmatic response (LAR) fall in forced expiratory volume in 1 s (FEV1) after allergen challenge at 1-week post-treatment. Results: AZD8848 significantly reduced average LAR fall in FEV1 by 27% vs. placebo at 1 week after treatment (p = 0.035). This effect was sustained at 4 weeks post-treatment; however, it did not reach clinical significance. AZD8848 reduced post-allergen challenge methacholine-induced airway hyper-responsiveness (AHR) vs. placebo at 1 week post-dosing (treatment ratio: 2.20, p = 0.024), with no effect at 4 weeks. There was no significant difference between the two groups in plasma cytokine, sputum Th2 cytokine or eosinophil responses post-allergen challenge at 1 week after treatment. The incidence of adverse events was similar in the two groups. AZD8848 was generally well tolerated. Conclusions and clinical relevance: In patients with allergic asthma, TLR7 agonists could potentially reduce allergen responsiveness by stimulating Type 1 interferon responses to down-regulate the dominant Th2 responses. Trial registration: clinicaltrials.gov identifier NCT00999466.
Toll-like receptors as targets for allergen immunotherapy
Curr Opin Allergy Clin Immunol 2015 Dec;15(6):568-74.PMID:26418475DOI:10.1097/ACI.0000000000000212.
Purpose of review: Toll-like receptors (TLRs) are novel and promising targets for allergen immunotherapy. Bench studies suggest that TLR agonists reduce Th2 responses and ameliorate airway hyper-responsiveness. In addition, clinical trials are at initial phases to evaluate the safety and efficacy of TLR agonists for the allergen immunotherapy of patients with allergic rhinitis and asthma. (Figure is included in full-text article.) Recent findings: To date, two allergy vaccine-containing TLR agonists have been investigated in clinical trials; Pollinex Quattro and AIC. The former contains monophosphoryl lipid, a TLR4 agonist and the latter contains, CpG motifs activating the TLR9 cascade. Preseasonal subcutaneous injection of both of these allergy vaccines has been safe and efficacious in control of nasal symptoms of patients with allergic rhinitis. CRX-675 (a TLR4 agonist), AZD8848 (a TLR7 agonist), VTX-1463 (a TLR8 agonist) and 1018 ISS and QbG10 (TLR9 agonists) are currently in clinical development for allergic rhinitis and asthma. Summary: TLR agonists herald promising results for allergen immunotherapy of patients with allergic rhinitis and asthma. Future research should be directed at utilizing these agents for immunotherapy of food allergy (for instance, peanut allergy) as well.
Biological effects and clinical efficacy of a topical Toll-like receptor 7 agonist in seasonal allergic rhinitis: a parallel group controlled phase IIa study
Inflamm Res 2015 Nov;64(11):903-15.PMID:26342289DOI:10.1007/s00011-015-0873-2.
Objective and design: The purpose of the study was to examine effects of pre-treatment with a Toll-like receptor 7 (TLR7) agonist (AZD8848) in allergic rhinitis and to evaluate clinical effects of two dosing regimens. Subjects: The study involved 83 patients with allergic rhinitis. Data on effects of AZD8848 on symptoms were analysed with data from a previous study (n = 68) of identical double blind, parallel group design (NCT00770003). Treatment: The treatment involved intranasal AZD8848 20 µg three times weekly, 60 µg once weekly, or placebo for 5 weeks. Methods: Nasal lavage and plasma were analysed for proof-of-mechanism markers. Daily nasal allergen challenges were given for 7 days, starting 24 h after the final AZD8848 dose. Symptoms were monitored after each challenge and every morning and evening. Results: Markers of TLR-activation increased following AZD8848 administration (CXCL10, TNFα, IL-6, IFNγ). Symptoms recorded soon after allergen challenge were reduced up to eight days after the final dose of AZD8848. Morning and evening symptoms were also reduced, and these changes reached statistical significance for morning observations. Adverse effects were more frequent in the 20 µg three times weekly group. Conclusions: Repeated administration of AZD8848 activated TLR7 and produced IFN-induced effects. This was associated with a sustained reduction in allergen responsiveness.