Carotegrast methyl
(Synonyms: AJM300) 目录号 : GC62143
Carotegrast methyl (AJM300) 是一种口服有效和选择性 α4 整联蛋白 (α4 integrin) 拮抗剂。HCA2969 是 Carotegrast methyl 的活性代谢产物，是一种特异的双重 α4β1/α4β7 整联蛋白拮抗剂。Carotegrast methyl 可预防小鼠结肠炎。
Cas No.:401905-67-7
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
Carotegrast methyl (AJM300) is an orally active and selective α4 integrin antagonist. HCA2969, an active metabolite of Carotegrast methyl, is a specific and dual α4β1/α4β7 integrin antagonist. Carotegrast methyl prevents the development of colitis in mice[1].
HCA2969 inhibits human α4β1 integrin (KD=0.32 nM; IC50=5.8 nM), human α4β7 integrin (KD=0.46 nM; IC50=1.4 nM) and mouse α4β7 integrin (KD=0.2 nM; IC50=26 nM) in Jurkat, RPMI-8866 and TK-1 cell lines[1].
Carotegrast methyl (AJM300; oral; 0.03-1%; for 15 days) prevents the development of colitis induced by transfer of IL-10 deficient CD4+ T cells in mice[1]. Carotegrast methyl (oral; 0.3, 3, 30, or 30 mg/kg; a single oral) inhibits Lymphocyte homing to Peyer’s patches and increases peripheral lymphocyte counts in a dose-dependent manner in BALB/c mice (8 weeks of age, female)[1].
[1]. Toshihiko Sugiura, et al. Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice. J Crohns Colitis. 2013 Dec;7(11):e533-42.
| Cas No. | 401905-67-7 | SDF | |
| 别名 | AJM300 | ||
| 分子式 | C28H26Cl2N4O5 | 分子量 | 569.44 |
| 溶解度 | DMSO : 100 mg/mL (175.61 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 | 1.7561 mL | 8.7806 mL | 17.5611 mL |
| 5 mM | 0.3512 mL | 1.7561 mL | 3.5122 mL |
| 10 mM | 0.1756 mL | 0.8781 mL | 1.7561 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。
Carotegrast methyl: First Approval
Drugs 2022 Jun;82(9):1011-1016.PMID:35723803DOI:10.1007/s40265-022-01732-0.
Carotegrast methyl (Carogra®) is a small-molecule α4 integrin antagonist being developed by EA Pharma (formerly Ajinomoto Pharmaceuticals) and Kissei Pharmaceutical for the treatment of ulcerative colitis. The active metabolite of Carotegrast methyl exerts an anti-inflammatory effect by blocking the interaction of α4β1 or α4β7 integrins and their ligands, VCAM-1 and MAd-CAM-1, thereby inhibiting the adhesion of inflammatory cells, including T cells, to vascular endothelial cells and extravasation into inflammatory sites. In March 2022, Carotegrast methyl received its first approval in Japan for the treatment of moderate ulcerative colitis in patients who had inadequate response to 5-aminosalicylic acid. This article summarizes the milestones in the development of Carotegrast methyl leading to this first approval for the treatment of moderate ulcerative colitis.
AJM300 (Carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled, phase 3 study
Lancet Gastroenterol Hepatol 2022 Jul;7(7):648-657.PMID:35366419DOI:10.1016/S2468-1253(22)00022-X.
Background: AJM300 is an oral, small-molecule α4-integrin antagonist. We assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis. Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study consisted of two phases: a treatment phase and an open-label re-treatment phase. The study was done at 82 hospitals and clinics in Japan. Patients with a Mayo Clinic score of 6-10, endoscopic subscore of 2 or more, rectal bleeding subscore of 1 or more, and an inadequate response or intolerance to mesalazine were enrolled. Patients were randomly allocated (1:1) via a website to either AJM300 (960 mg) or placebo by the minimisation method, which was adjusted centrally by dynamic assignment against the Mayo Clinic score (≥6 to ≤7, ≥8 to ≤10 points), any use of corticosteroid, anti-TNFα antibody, or immunosuppressants during the disease-active period (yes vs no), duration of induction therapy until randomisation (<4 weeks vs ≥4 weeks) as the minimisation factors. Patients, investigators, site staff, assessors, and the sponsor were masked to treatment assignments. The study drug was administered orally, three times daily, for 8 weeks, and continued for up to 24 weeks if endoscopic remission was not achieved or rectal bleeding did not stop. The primary endpoint was the proportion of patients with a clinical response at week 8, and was analysed in the full analysis set. Clinical response was defined as a reduction in Mayo Clinic score of 30% or more and 3 or more, a reduction in rectal bleeding score of 1 or more or rectal bleeding subscore of 1 or less, and an endoscopic subscore of 1 or less at week 8. The study is registered with ClinicalTrials.gov, NCT03531892, and is closed to recruitment. Findings: Between June 6, 2018, and July 22, 2020, 203 patients were randomly assigned to AJM300 (n=102) or placebo (n=101). At week 8, 46 (45%) patients in the AJM300 group and 21 (21%) patients in the placebo group had a clinical response (odds ratio 3·30, 95% CI 1·73-6·29; p=0·00028). During the 8-week treatment and 16-week extension treatment periods, adverse events occurred in 39 (39%) of 101 patients in the placebo group and 39 (38%) of 102 patients in the AJM300 group. We found no difference in the incidence of adverse events between groups or after repeated administration of AJM300. The most common adverse event was nasopharyngitis (11 [11%] of 101 patients in the placebo group and ten [10%] of 102 patients in the AJM300 group). The most common treatment-related adverse event was also nasopharyngitis (four [4%] of 101 patients in the placebo group and three [3%] of 102 patients in the AJM300 group). Most adverse events were mild-to-moderate in severity. No deaths were reported. A serious adverse event was reported in the AJM300 group (one patient with anal abscess), but this was judged to be unrelated to study drug. Interpretation: AJM300 was well tolerated and induced a clinical response in patients with moderately active ulcerative colitis who had an inadequate response or intolerance to mesalazine. AJM300 could be a novel induction therapy for the treatment of patients with moderately active ulcerative colitis. Funding: EA Pharma and Kissei Pharmaceutical. Translation: For the Japanese translation of the abstract see Supplementary Materials section.
Food Effect on a Single High Dose of Carotegrast methyl, an Oral Antagonist of α4-Integrin, in Healthy Male Subjects: A Randomised, Placebo-Controlled, Double-Blind Study
Clin Drug Investig 2020 Mar;40(3):237-247.PMID:31965548DOI:10.1007/s40261-019-00879-1.
Background and objectives: Carotegrast methyl, a novel prodrug, oral antagonist of α4-integrin, is in development for the treatment of active ulcerative colitis. This randomised, placebo-controlled, double-blind, crossover study evaluated the effect of food on the pharmacokinetics and pharmacodynamics as well as the safety profile after a single dose of Carotegrast methyl in healthy male subjects. Methods: Subjects were randomised to receive a single dose of Carotegrast methyl (240, 480 or 960 mg) or placebo in a 6:2 ratio and received the study drug under both fed and fasted conditions separated by an 8-day washout. The pharmacokinetic profiles of Carotegrast methyl and its active metabolite, carotegrast, were assessed. The pharmacodynamic profile was evaluated according to a change in the peripheral lymphocyte count. Safety was monitored throughout. Results: Based on the area under the time curve from zero to the time of the last quantifiable concentration (AUClast), food reduced systemic exposure to both Carotegrast methyl and carotegrast by 21-57% and 5-29%, respectively. The fed-to-fasted ratio of least square means for the increase in the lymphocyte count was almost at unity in each dose, indicating no food effect on pharmacodynamics. The time ≥ 90% of maximum effect was prolonged dose dependently, suggesting that a 960 mg-dose can provide a long-lasting effect. Reported adverse events were all mild. Conclusions: Despite the reduced systemic exposure to both Carotegrast methyl and carotegrast, food had no effect on the increase in lymphocyte count. A single administration of Carotegrast methyl up to 960 mg was found to be safe.
Appraisal of ICH E14/S7B Q&As adopted in February 2022 using thorough QT/QTc study data for α4-integrin antagonist Carotegrast methyl in Japanese healthy subjects
J Pharmacol Sci 2022 Nov;150(3):191-199.PMID:36184124DOI:10.1016/j.jphs.2022.08.007.
We investigated how a lack of placebo control affects the interpretation of results of thorough QT/QTc (TQT) study. Results of TQT study in 48 healthy Japanese subjects assessing the effects of 480 and 960 mg of Carotegrast methyl (test drug) and 400 mg of moxifloxacin (positive control) on the time-matched changes in corrected QT from baseline (ΔQTcF) and the placebo-adjusted ΔQTcF (ΔΔQTcF) were analyzed with central-tendency and concentration-response analyses. In central-tendency analysis, moxifloxacin prolonged ΔQTcF and ΔΔQTcF with the largest mean values (90% confidence interval) of 12.1 ms (9.3, 14.8) and 15.4 ms (12.6, 18.1), respectively. Meanwhile, Carotegrast methyl hardly altered ΔQTcF and ΔΔQTcF with the largest mean values of 0.8 ms (-2.3, 3.9) and 2.1 ms (-0.7, 4.8) for the low dose, and -0.2 ms (-3.4, 3.0) and 1.6 ms (-0.9, 4.2) for the high dose, respectively. In concentration-response analysis, moxifloxacin attained the estimated mean values for ΔQTcF and ΔΔQTcF of 11.4 ms (8.5, 14.4) and 16.7 ms (14.0, 19.4) at the mean Cmax, whereas Carotegrast methyl provided those of -4.6 ms (-7.3, -1.9) and 0.7 ms (-1.4, 2.8), respectively. Thus, lack of placebo control did not influence the interpretation of TQT study with either of the analysis in line with updated E14/S7B Q&As.
[Pharmacological and Clinical data of oral alpha 4 integrin antagonist, Carotegrast methyl, CAROGRA®]
Nihon Yakurigaku Zasshi 2023;158(2):203-210.PMID:36858506DOI:10.1254/fpj.22120.
Carotegrast-methyl (brand name: CAROGRA® Tablets) is a new chemical entity created by Ajinomoto Pharmaceuticals Co., Ltd. (currently EA Pharma Co., Ltd.) as an α4 integrin inhibitor. In vivo, it exerts an anti-inflammatory effect by inhibiting the functions of both α4β1 integrin and α4β7 integrin expressed on the surface of inflammatory cells such as lymphocytes. Under the joint development of EA Pharma Co., Ltd. and Kissei Pharmaceutical Co., Ltd., the efficacy and safety of Carotegrast methyl were confirmed in patients with moderate active ulcerative colitis. Carotegrast-methyl, the Japan-originated, world-first orally available α4 integrin antagonist, was approved in March and launched in May 2022 in Japan. Patients who had inadequate response or intolerance to the basic treatment with 5-ASA preparations for ulcerative colitis, have widely desired an orally available treatment with the new mechanism of actions. Carotegrast methyl can be a treatment option that meets that unmet medical need and has the potential to greatly contribute to the treatment of ulcerative colitis based on the thorough practice of proper use. This article mainly introduces the pharmacological properties and clinical trial results of Carotegrast methyl.