Razuprotafib
(Synonyms: AKB-9778) 目录号 : GC62687
Razuprotafib (AKB-9778) 是 VE-PTP (HPTPß) 催化活性的有效选择性抑制剂 (IC50=17 pM)，促进 TIE2 活化，增强 ANG1 诱导的 TIE2 活化，并刺激 TIE2 通路中信号分子的磷酸化，包括 AKT、eNOS 和 ERK。Razuprotafib 抑制结构相关磷酸酶 PTP1B，IC50 为 780 nM。除 HPTPΗ (IC50=36 pM) 和 HPTPγ (100 pM) 外，Razuprotafib 对 VE-PTP 具有良好的选择性。
Cas No.:1008510-37-9
Sample solution is provided at 25 µL, 10mM.
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Razuprotafib (AKB-9778) is a potent and selective inhibitor of the catalytic activity of VE-PTP (vascular endothelial protein tyrosine phosphatase) with an IC50of 17 pM. Razuprotafib promotes TIE2 activation, enhances ANG1-induced TIE2 activation, and stimulates phosphorylation of signaling molecules in the TIE2 pathway, including AKT, eNOS, and ERK. Razuprotafib inhibits the structurally related phosphatase PTP1B with an IC50 of 780 nM. Razuprotafib shows excellent selectivity for VE-PTP versus a variety of phosphatases, with the exception of HPTPΗ (IC50=36 pM) and HPTPγ (100 pM)[1].
Razuprotafib (AKB-9778) promotes TIE2 phosphorylation and activation of downstream signaling in HUVECs and enhances angiopoietin-induced TIE2 phosphorylation[1].
Razuprotafib (20 mg/kg; s.c.) promotes phosphorylation of TIE2 in retinal endothelial cells in vivo[1].Razuprotafib (10-20 mg/kg; s.c.; twice daily for 7 days) suppresses subretinal neovascularization (NV)[1].
[1]. Shen J, et al. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest. 2014;124(10):4564-4576.
| Cas No. | 1008510-37-9 | SDF | |
| 别名 | AKB-9778 | ||
| 分子式 | C26H26N4O6S3 | 分子量 | 586.7 |
| 溶解度 | DMSO : 100 mg/mL (170.44 mM; Need ultrasonic) | 储存条件 | -20°C avoid light |
| 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 | 1.7044 mL | 8.5222 mL | 17.0445 mL |
| 5 mM | 0.3409 mL | 1.7044 mL | 3.4089 mL |
| 10 mM | 0.1704 mL | 0.8522 mL | 1.7044 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。
Oxidative metabolism of Razuprotafib (AKB-9778), a sulfamic acid phosphatase inhibitor, in human microsomes and recombinant human CYP2C8 enzyme
Xenobiotica 2021 Oct;51(10):1110-1121.PMID:34477046DOI:10.1080/00498254.2021.1969482.
Razuprotafib, a sulphamic acid-containing phosphatase inhibitor, is shown in vivo to undergo enzymatic oxidation and methylation to form a major metabolite in monkey and human excreta with an m/z- value of 633.LC-MS/MS analysis of samples derived from incubations of Razuprotafib with human liver microsomes and recombinant CYP2C8 enzyme has elucidated the metabolic pathway for formation of the thiol precursor to the S-methyl metabolite MS633 (m/z- 633).Under in vitro conditions, the major pathway of Razuprotafib metabolism involves extensive oxidation of the thiophene and phenyl rings.A single oxidation takes place at one of the phenyl groups. Multiple oxidations occur at the thiophene moiety: initial oxidation results in the formation of a thiolactone followed by a second oxidation giving rise to an S-oxide of the thiolactone, which is further metabolised to the ring-opened form and ultimate formation of a thiol (m/z- 619).An additional mono-oxidation pathway involves epoxidation of the thiophene followed by hydrolysis to a diol.The thiol and diol metabolites are trapped by the addition of a nucleophilic trapping agent, 3-methoxyphenacyl bromide (MPB), giving adducts with m/z- 767.The thiol is a likely precursor to the major in vivo Razuprotafib metabolite, MS633.
The in vivo disposition of subcutaneous injected 14C-razuprotafib (14C-AKB-9778), a sulphamic acid phosphatase inhibitor, in nonclinical species and human
Xenobiotica 2021 Oct;51(10):1132-1145.PMID:34420473DOI:10.1080/00498254.2021.1972358.
The disposition of radioactivity following subcutaneous 14C-razuprotafib, a Tie2 activator, was explored in multiple species.The absorption and clearance of Razuprotafib and total radioactivity in human plasma are rapid and pharmacokinetics support Razuprotafib as primary circulating component. Radioactivity is distributed greater to human plasma than whole blood (B:P = 0.36).In pigmented rats, radioactivity distributes to whole-body tissues rapidly and, within 24 h, is localised to elimination pathway end organs and injection site.Overall recovery of radioactivity across species is >93%, with the majority recovered within 24-48 h, and >80% in faeces.The CYP2C8 enzyme contributes significantly to Razuprotafib metabolism.A hydrolysis product of Razuprotafib (m/z- 380) is the main component in rat plasma at 2 h (49% peak area radioactivity), while Razuprotafib (m/z- 585) is the main component in plasma for dog (58%), monkey (99.3%), and human (100%).Razuprotafib is present in dog, monkey, and human faeces, with the greatest percentage of radioactivity as metabolites. The major metabolite (>25%) in monkey and human, m/z- 633, is an S-methylated oxidised derivative of Razuprotafib and is localised in faeces.Overall disposition of 14C-razuprotafib in human is best modelled by monkey over lower order species.
Tie2 Activation via VE-PTP Inhibition With Razuprotafib as an Adjunct to Latanoprost in Patients With Open Angle Glaucoma or Ocular Hypertension
Transl Vis Sci Technol 2022 Jan 3;11(1):7.PMID:34989803DOI:10.1167/tvst.11.1.7.
Purpose: To evaluate the ocular hypotensive efficacy and safety of Razuprotafib, a novel Tie2 activator, when used as an adjunct to latanoprost in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods: Subjects with OAG or OHT and an unmedicated IOP from ≥22 mm Hg to <36 mm Hg were randomized to one of three treatment arms: Razuprotafib every day (QD) + latanoprost; Razuprotafib twice daily (BID) + latanoprost; or latanoprost monotherapy. The primary endpoint was change in mean diurnal IOP from baseline at day 28. Results: A total of 194 subjects were randomized, and 193 (99.5%) completed the study. Razuprotafib BID + latanoprost resulted in a significantly larger reduction in diurnal IOP than latanoprost alone (7.95 ± 0.26 mmHg vs. 7.04 ± 0.26 mm Hg, P < 0.05). A smaller improvement was observed after 14 days of treatment (7.62 ± 0.26 mm Hg vs. 7.03 ± 0.26 mm Hg, P = 0.11). Razuprotafib QD dosing did not demonstrate additional IOP lowering compared to latanoprost alone. Conjunctival hyperemia on Day 28 increased by 1.1 units on the four-point Efron scale two hours post dose from a baseline value of 0.6 units, and decreased thereafter. Conclusions: Topical ocular Razuprotafib as an adjunct to latanoprost therapy was well tolerated and significantly reduced IOP in patients with OAG/OHT. Translational relevance: These data support the IOP lowering efficacy of targeting Tie2 activation in Schlemm's canal in the relevant patient population.
The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye
Int J Retina Vitreous 2020 Oct 13;6:48.PMID:33072401DOI:10.1186/s40942-020-00250-z.
Background: Retinal vascular diseases such as neovascular age-related macular degeneration, diabetic retinopathy and/or diabetic macular edema, and retinal vein occlusion with macular edema-share several key pathophysiologic aspects including neovascularization, vascular permeability, and inflammation. The role of vascular endothelial growth factor (VEGF) in these processes, and the therapeutic benefits of VEGF inhibition, have been well characterized. Anti-VEGF therapy is highly effective for many patients but is not uniformly effective in all patients and imposes a significant treatment burden. More recently, the role of the Tie2 signaling pathway in the pathophysiology of retinal vascular diseases has been investigated, and the Tie2 pathway represents a novel therapeutic target for these conditions. Areas covered: The index review describes the Tie2 pathway and its complementary role to the VEGF pathway in the angiogenesis cascade and will summarize studies of molecules in development to therapeutically modulate the Tie2 pathway in retinal vascular diseases. Conclusions: Activation of the Tie2 pathway leads to downstream signaling that promotes vascular health and stability and decreases vascular permeability and inflammation. AXT107 is a collagen IV-derived synthetic peptide with a dual mechanism of action that involves suppression of VEGF signaling and activation of the Tie2 pathway; these actions are accomplished by AXT107 binding to and disrupting different integrin, leading to blockade of the VEGF receptor and rearrangement of cellular Tie2 rendering it susceptible to Ang2 agonism. Other Tie2 agonist compounds are also in development, including faricimab and Razuprotafib. Tie2 activation only modestly impacts angiogenesis on its own but significantly potentiates VEGF suppression. Co-regulation of the VEGF and Tie2 signaling pathways has the potential to improve functional and structural outcomes in eyes with retinal vascular diseases.
Endothelial Dysfunction in Fabry Disease Is Related to Glycocalyx Degradation
Front Immunol 2021 Nov 30;12:789142.PMID:34917096DOI:10.3389/fimmu.2021.789142.
Fabry disease (FD) is an X-linked multisystemic lysosomal storage disease due to a deficiency of α-galactosidase A (GLA/AGAL). Progressive cellular accumulation of the AGAL substrate globotriaosylceramide (Gb3) leads to endothelial dysfunction. Here, we analyzed endothelial function in vivo and in vitro in an AGAL-deficient genetic background to identify the processes underlying this small vessel disease. Arterial stiffness and endothelial function was prospectively measured in five males carrying GLA variants (control) and 22 FD patients under therapy. AGAL-deficient endothelial cells (EA.hy926) and monocytes (THP1) were used to analyze endothelial glycocalyx structure, function, and underlying inflammatory signals. Glycocalyx thickness and small vessel function improved significantly over time (p<0.05) in patients treated with enzyme replacement therapy (ERT, n=16) and chaperones (n=6). AGAL-deficient endothelial cells showed reduced glycocalyx and increased monocyte adhesion (p<0.05). In addition, increased expression of angiopoietin-2, heparanase and NF-κB was detected (all p<0.05). Incubation of wild-type endothelial cells with pathological globotriaosylsphingosine concentrations resulted in comparable findings. Treatment of AGAL-deficient cells with recombinant AGAL (p<0.01), heparin (p<0.01), anti-inflammatory (p<0.001) and antioxidant drugs (p<0.05), and a specific inhibitor (Razuprotafib) of angiopoietin-1 receptor (Tie2) (p<0.05) improved glycocalyx structure and endothelial function in vitro. We conclude that chronic inflammation, including the release of heparanases, appears to be responsible for the degradation of the endothelial glycocalyx and may explain the endothelial dysfunction in FD. This process is partially reversible by FD-specific and anti-inflammatory treatment, such as targeted protective Tie2 treatment.