GSK2245035
目录号 : GC60183
A TLR7 agonist
Cas No.:1207629-49-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
GSK2245035 is a toll-like receptor 7 (TLR7) agonist.1 It selectively induces the production of IFN-α over TNF-α in isolated human peripheral blood mononuclear cells (PBMCs; EC50s = 0.63 and 316 nM, respectively), as well as over the production of TNF-α, IL-1β, IFN-γ, IL-10, and IL-12p70 in isolated human whole blood (EC50s = 63-10,000 nM). GSK2245035 (0.1-1,000 nM) reduces timothy grass- or house dust mite-induced IL-10 and IL-5 release in isolated human PBMCs. Intranasal administration of GSK2245035 (0.03-1 mg/kg) increases serum IP-10 levels, a marker of IFN-α induction, in mice. It also increases serum levels of IP-10 in cynomolgus monkeys.
1.Biggadike, K., Ahmed, M., Ball, D.I., et al.Discovery of 6-amino-2-{[(1S)-1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-purin-8-one (GSK2245035), a highly potent and selective intranasal toll-like receptor 7 agonist for the treatment of asthmaJ. Med. Chem.59(5)1711-1726(2016)
| Cas No. | 1207629-49-9 | SDF | |
| Canonical SMILES | O=C1NC2=C(N=C(N=C2N1CCCCCN3CCCCC3)O[C@H](CCC)C)N | ||
| 分子式 | C20H34N6O2 | 分子量 | 390.52 |
| 溶解度 | DMSO: 125 mg/mL (320.09 mM) | 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 | 2.5607 mL | 12.8034 mL | 25.6069 mL |
| 5 mM | 0.5121 mL | 2.5607 mL | 5.1214 mL |
| 10 mM | 0.2561 mL | 1.2803 mL | 2.5607 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。
GSK2245035, a TLR7 agonist, Does Not Increase Pregnancy Loss in Cynomolgus Monkeys
J Reprod Immunol 2021 Feb;143:103242.PMID:33212303DOI:10.1016/j.jri.2020.103242.
GSK2245035, a small molecule Toll-like Receptor 7 (TLR7) agonist developed for immunomodulatory treatment for allergic airways disease, aimed to reduce Th2 and enhance Th1/Treg responses to aeroallergens via the local induction of type I interferons (IFNs). GSK2245035 demonstrated selectivity for potent release of type I IFNs compared to TNF-α and IL-6, with dose dependent increases in the interferon inducible chemokine, IP-10, in the nasal compartment. Implantation and parturition require pro-inflammatory processes including IFNs, Interferon Stimulated Genes, TNFα and IP-10 while pregnancy requires immune regulation to maintain maternal fetal immune tolerance, and recombinant type I IFNs induced abortions in monkeys. Due to its mechanism of action, GSK2245035 was studied at pharmacologically and clinically relevant doses in a monkey pregnancy model. Monkeys received 0, 3 or 30 ng/kg/week GSK2245035 intranasally once weekly, from Day 20 postcoitum through Day 63 postpartum. Although systemic IFN-α and IP-10 levels were approximately 14.8 or 40 -fold (respectively) above predose levels at 3 or 30 ng/kg/week, respectively, there were no effects on pregnancy and infant outcome. Non-adverse effects included increased incidence of nasal discharge, increased maternal body temperature at 30 ng/kg/week and dose-dependent increases in maternal IP-10 and IFN-α and decreased infant anti-KLH IgM and IgG titers following KLH immunization at ≥3 ng/kg/week, relative to controls. Potentially, lower IFN-α and IP-10 levels as well as once-weekly intranasal dosing vs daily subcutaneous or intramuscular dosing with recombinant type I IFNs could explain the lack of pregnancy effects; however, there was an undesired impact on offspring immune function.
Intranasal GSK2245035, a Toll-like receptor 7 agonist, does not attenuate the allergen-induced asthmatic response in a randomized, double-blind, placebo-controlled experimental medicine study
PLoS One 2020 Nov 9;15(11):e0240964.PMID:33166307DOI:10.1371/journal.pone.0240964.
Background: Allergic asthma is a heterogenous disorder predominantly driven by a type 2 inflammatory response to aeroallergens. Therapeutic modulation to rebalance these type 2 responses may offer clinical benefit for allergic respiratory inflammatory diseases, with the potential for disease modification. GSK2245035, a selective toll-like receptor-7 agonist, preferentially stimulates the induction of type 1 interferon alpha, reducing type 2 responses. Objective: This study investigated whether intranasal GSK2245035 reduced allergen-induced bronchial reactivity in mild allergic asthma. Methods: This double-blind, placebo-controlled, parallel-group Phase IIa trial randomized (1:1) participants with mild allergic asthma to intranasal GSK2245035 20 ng or placebo once weekly for 8 weeks; follow-up was conducted 1, 4, and 12 weeks after treatment. Allergen-induced late asthmatic response 1 week after treatment was measured as minimum and weighted mean forced expiratory volume in 1 second (FEV1) 4-10 hours following bronchial allergen challenge (primary endpoint). Pharmacodynamic and allergic biomarkers, and adverse events, were assessed. A Bayesian analysis framework was used; a posterior probability >0.7 denoted primary endpoint success. Results: Thirty-six participants were randomized (GSK2245035, n = 22; placebo, n = 14). The percentage attenuation in late asthmatic response was -4.6% (posterior probability: 0.385) and -10.5% (posterior probability: 0.303) for minimum and weighted mean FEV1, respectively. Type 2 responses were confirmed by changes in lung function, eosinophils (blood and sputum), interleukin-5 (sputum) and fractional exhaled nitric oxide biomarkers pre- and post-bronchial allergen challenge. However, no treatment effect was observed. Adverse events were reported by 10/14 (71%) and 21/22 (95%) participants in the placebo and GSK2245035 groups, respectively; headache was the most common. Conclusions and clinical relevance: Although target engagement was observed, weekly intranasal GSK2245035 20 ng for 8 weeks did not substantially attenuate the late asthmatic response in participants with mild allergic asthma. Overall, treatment was well tolerated.
Safety and pharmacodynamics of intranasal GSK2245035, a TLR7 agonist for allergic rhinitis: A randomized trial
Clin Exp Allergy 2017 Sep;47(9):1193-1203.PMID:28681506DOI:10.1111/cea.12974.
Background: Toll-like receptor 7 (TLR7) stimulation in the airways may reduce responses to aeroallergens by induction of type 1 interferons (IFNs). GSK2245035 is a novel selective TLR7 agonist in pharmaceutical development. Objective: Assessment of safety, pharmacodynamics and nasal allergic reactivity following repeated weekly intranasal (i.n.) GSK2245035. Methods: This randomized, double-blind, placebo-controlled study (TL7116958) was conducted over two pollen seasons (2013-2014) and follow-up study (204509) conducted 1 year later. Participants with allergic rhinitis (n=42) were randomized to receive eight weekly doses of i.n. GSK2245035 (20 ng [2014 Cohort; n=14] or 80 ng [2013 Cohort; n=14]) or placebo (n=14). Adverse events (AEs) including cytokine release syndrome AEs (CytoRS-AEs) and nasal symptoms were assessed. Nasal and serum IFN-inducible protein 10 (IP-10) were measured after doses 1 and 8, then 1 (follow-up visit [FUV] 1) and 3 (FUV2) weeks after final dose. Nasal allergen challenges (NACs) and allergic biomarker assessment (nasal, serum) were conducted at baseline, FUV1, FUV2 and at a FUV 1 year after final dose (FUV3; 2014 Cohort only). A Bayesian framework enabled probability statements for mean effect sizes. Results: GSK2245035 induced CytoRS-AEs (most commonly headache, median duration <1 day) in 93% of participants at 80 ng, while AE incidence at 20 ng was similar to placebo. There was no evidence of nasal inflammation. Dose-related increases in nasal and serum IP-10 were observed 24 hours after doses 1 and 8 (>95% certainty). Both doses showed a trend in reducing total nasal symptom score 15 minutes post-NAC at FUV1 and FUV2, but there was no reduction evident at FUV3. Nasal levels of selected allergic biomarkers demonstrated trends for reductions at FUV1, FUV2 and FUV3. Conclusions and clinical relevance: Weekly i.n. GSK2245035 20 ng was well tolerated and reduced allergic reactivity to nasal challenge for 3 weeks post-treatment.
Early clinical evaluation of the intranasal TLR7 agonist GSK2245035: Use of translational biomarkers to guide dosing and confirm target engagement
Clin Pharmacol Ther 2015 Oct;98(4):369-80.PMID:26044169DOI:10.1002/cpt.157.
Modulation of the airways' immune milieu is a key therapeutic goal for remission from respiratory allergies. To explore this hypothesis, GSK2245035, a selective Toll-like receptor 7 (TLR7) agonist with preferential Type-1 interferon (IFN)-stimulating properties, was developed for intranasal application. Doses for clinical assessment were extrapolated from translational biomarker studies in primates. Randomized, double-blind, placebo-controlled trials in healthy volunteers and patients with allergic rhinitis demonstrated that intranasal GSK2245035 doses <100 ng were tolerated and did not cause nasal inflammation. Higher doses were not tested due to considerable cytokine release syndrome-related symptoms observed at 100 ng. Clear target engagement, reflected by local and peripheral increase of IFN-gamma-inducible protein-10, was observed at 20 ng, indicating IFN-stimulated immune changes at tolerated doses. Repeat intranasal administration at weekly intervals did not tolerize or amplify the pharmacological response. Intranasal GSK2245035 has an acceptable safety profile at doses that induce local TLR7-mediated immune responses.
Discovery of 6-Amino-2-{[(1S)-1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-purin-8-one (GSK2245035), a Highly Potent and Selective Intranasal Toll-Like Receptor 7 Agonist for the Treatment of Asthma
J Med Chem 2016 Mar 10;59(5):1711-26.PMID:26861551DOI:10.1021/acs.jmedchem.5b01647.
Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.