CMX001
(Synonyms: Brincidofovir; HDP-CDV) 目录号 : GC17689
CMX001 是一种亲脂性核苷酸类似物，由 3-(hexdecyloxy)propan-1-ol 与西多福韦 (CDV) 共价连接而成，用于治疗天花。
Cas No.:444805-28-1
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
| Cell experiment [1]: | |
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Cell lines |
Primary human renal proximal tubule epithelial cells |
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Preparation Method |
About 24 h after seeding 150 µl of the medium was replaced with fresh medium with or without purified BKV-Dunlop in the presence or absence of CMX001 (final concentration of 0.31 µM). The cells were grown for 96 h, and impedance was measured every 15 min for the first 6 h and then every 30 min. |
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Reaction Conditions |
0.31 µM; 24h |
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Applications |
CMX001 reduced the extracellular BKV load in a concentration-dependent manner.The CMX001 concentration of 0.31 µM consistently provided this level of inhibition. |
| Animal experiment [2]: | |
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Animal models |
8 week (3-4 lb) old New Zealand White rabbits |
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Dosage form |
20 mg/kg per dose; i.v. |
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Preparation Method |
Animals were given a total of one, two or three doses of CMX001 (20 mg/kg per dose) spaced every other day beginning on the day secondary lesions were detected in the ears of the animals. |
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Applications |
As with the intradermal infection model, one, two, or three doses of CMX001 appeared to significantly reduce disease symptoms and have a survival benefit. |
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References: [1] Rinaldo CH, et al. 1-O-hexadecyloxypropyl cidofovir (CMX001) effectively inhibits polyomavirus BK replication in primary human renal tubular epithelial cells. Antimicrob Agents Chemother. 2010 Nov;54(11):4714-22. |
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CMX001 is a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV) used for treatment of smallpox.[1]
In vitro experiment it shown that 0.079 μM CMX001 inhibited JCV replication in COS-7 cells. And treatment with 0.038 μM or 0.6 μM CMX001 in PDA cells resulted in a obviously decreased the number of infectious JCV progeny in a concentration-dependent manner. Treatment with 0.079 to 10 μM CMX001 in COS-7 cells reduced the metabolic activity to 52% and BrdU incorporation to 10% at the highest concentration.[2] CMX001 was active with EC90 of 0.31 μM at about 400-times-lower concentrations than the EC90 for CDV in the same test system.[3] In vitro efficacy test it exhibited that treatment with 0.01 μM to 0.1 μM resulted in minimal cytotoxic effects in human fetal brain SVG cells.[4] In vitro, CMX001 has against five variola virus strains with EC50 of averaged 0.11 μM.[5]
In vivo clinical study it shown that treatment with oral CMX001 at a dose of 100 mg twice weekly obviously reduced the incidence of CMV events in recipients of hematopoietic-cell transplants.[6] In ECTV-infected A/NCR mice, a 2.5 mg/kg dose of CMX001 given once daily for five days starting 4 h post-infection provides complete protection against a lethal intranasal challenge. Mice were treated with 10 mg/kg CMX001 when the fifth day, then followed by a 2.5 mg/kg dose every other day for 14 days can be completely protected from mortality. However, treatment with 20 mg/kg CMX001 orally as late as four days post-infection provided 100% protection against lethal ECTV infection.[7]
References:
[1].Rice AD, et al. Efficacy of CMX001 as a post exposure antiviral in New Zealand White rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans. Viruses. 2011 Jan;3(1):47-62.
[2].Gosert R, et al. CMX001 (1-O-hexadecyloxypropyl-cidofovir) inhibits polyomavirus JC replication in human brain progenitor-derived astrocytes. Antimicrob Agents Chemother. 2011 May;55(5):2129-36.
[3].Rinaldo CH, et al. 1-O-hexadecyloxypropyl cidofovir (CMX001) effectively inhibits polyomavirus BK replication in primary human renal tubular epithelial cells. Antimicrob Agents Chemother. 2010 Nov;54(11):4714-22.
[4].Jiang ZG, et al. Hexadecyloxypropyl-cidofovir (CMX001) suppresses JC virus replication in human fetal brain SVG cell cultures. Antimicrob Agents Chemother. 2010 Nov;54(11):4723-32.
[5].Olson VA, et al. In vitro efficacy of brincidofovir against variola virus. Antimicrob Agents Chemother. 2014 Sep;58(9):5570-1.
[6].Marty FM, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med. 2013 Sep 26;369(13):1227-36.
[7].Lanier R, et al. Development of CMX001 for the Treatment of Poxvirus Infections. Viruses. 2010 Dec;2(12):2740-2762.
CMX001 是一种亲脂性核苷酸类似物，由 3-(hexdecyloxy)propan-1-ol 与西多福韦 (CDV) 共价连接而成，用于治疗天花。[1]
体外实验表明，0.079 μM CMX001 可抑制 COS-7 细胞中的 JCV 复制。在 PDA 细胞中用 0.038 μM 或 0.6 μM CMX001 处理导致感染性 JCV 后代数量明显减少，且呈浓度依赖性。在 COS-7 细胞中用 0.079 至 10 μM CMX001 处理，在最高浓度下，代谢活性降低至 52%，BrdU 掺入降低至 10%。[2] CMX001 在大约 0.31 μM 时具有活性，EC90 为 0.31 μM在同一测试系统中，浓度比 CDV 的 EC90 低 400 倍。[3] 体外药效测试表明，0.01 μM 至 0.1 μM 的处理对人胎儿大脑的细胞毒性作用最小SVG 细胞。[4] 在体外，CMX001 对五种天花病毒株具有平均 EC50 0.11 μM。[5]
体内临床研究表明，每周两次口服 CMX001 100 mg 可显着降低造血细胞移植受者的 CMV 事件发生率。[6] 在 ECTV-对于感染的 A/NCR 小鼠，从感染后 4 小时开始每天一次给予 2.5 mg/kg 剂量的 CMX001，持续五天，可提供针对致命鼻内攻击的完全保护。小鼠在第五天时用 10 mg/kg CMX001 处理，然后每隔一天用 2.5 mg/kg 剂量处理，持续 14 天可以完全保护免于死亡。然而，最晚在感染后 4 天口服 20 mg/kg CMX001 可提供 100% 的保护，防止致命的 ECTV 感染。[7]
| Cas No. | 444805-28-1 | SDF | |
| 别名 | Brincidofovir; HDP-CDV | ||
| 化学名 | [(2S)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid | ||
| Canonical SMILES | CCCCCCCCCCCCCCCCOCCCOP(=O)(COC(CN1C=CC(=NC1=O)N)CO)O | ||
| 分子式 | C27H52N3O7P | 分子量 | 561.69 |
| 溶解度 | <1.12mg/mL in DMSO, Limited solubility in EtOH | 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 | 1.7803 mL | 8.9017 mL | 17.8034 mL |
| 5 mM | 0.3561 mL | 1.7803 mL | 3.5607 mL |
| 10 mM | 0.178 mL | 0.8902 mL | 1.7803 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。
CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation
N Engl J Med2013 Sep 26;369(13):1227-36.PMID: 24066743DOI: 10.1056/NEJMoa1303688
Background: The use of available antiviral agents for the prevention of cytomegalovirus (CMV) disease is limited by frequent toxic effects and the emergence of resistance. CMX001 has potent in vitro activity against CMV and other double-stranded DNA viruses. We evaluated the safety and anti-CMV activity of CMX001 in patients who had undergone allogeneic hematopoietic-cell transplantation.
Methods: From December 2009 through June 2011, a total of 230 patients with data that could be evaluated were enrolled in the study. We randomly assigned these adult CMV-seropositive transplant recipients from 27 centers to oral administration of CMX001 or placebo. Patients were assigned in a 3:1 ratio to five sequential study cohorts according to a dose-escalating, double-blind design. Randomization was stratified according to the presence or absence of acute graft-versus-host disease and CMV DNA in plasma. Patients received the study drug after engraftment for 9 to 11 weeks, until week 13 after transplantation. Polymerase-chain-reaction analysis of CMV DNA in plasma was performed weekly. Patients in whom CMV DNA was detected at a level that required treatment discontinued the study drug and received preemptive treatment against CMV infection. The primary end point was a CMV event, defined as CMV disease or a plasma CMV DNA level greater than 200 copies per milliliter when the study drug was discontinued. The analysis was conducted in the intention-to-treat population.
Results: The incidence of CMV events was significantly lower among patients who received CMX001 at a dose of 100 mg twice weekly than among patients who received placebo (10% vs. 37%; risk difference, -27 percentage points; 95% confidence interval, -42 to -12; P=0.002). Diarrhea was the most common adverse event in patients receiving CMX001 at doses of 200 mg weekly or higher and was dose-limiting at 200 mg twice weekly. Myelosuppression and nephrotoxicity were not observed.
Conclusions: Treatment with oral CMX001 at a dose of 100 mg twice weekly significantly reduced the incidence of CMV events in recipients of hematopoietic-cell transplants. Diarrhea was dose-limiting in this population at a dose of 200 mg twice weekly. (Funded by Chimerix; CMX001-201 ClinicalTrials.gov number, NCT00942305.).
Pharmacokinetics and Efficacy of a Potential Smallpox Therapeutic, Brincidofovir, in a Lethal Monkeypox Virus Animal Model
mSphere2021 Feb 3;6(1):e00927-20.PMID: 33536322DOI: 10.1128/mSphere.00927-20
Smallpox, caused by Variola virus (VARV), was eradicated in 1980; however, VARV bioterrorist threats still exist, necessitating readily available therapeutics. Current preparedness activities recognize the importance of oral antivirals and recommend therapeutics with different mechanisms of action. Monkeypox virus (MPXV) is closely related to VARV, causing a highly similar clinical human disease, and can be used as a surrogate for smallpox antiviral testing. The prairie dog MPXV model has been characterized and used to study the efficacy of antipoxvirus therapeutics, including recently approved TPOXX (tecovirimat). Brincidofovir (BCV; CMX001) has shown antiviral activity against double-stranded DNA viruses, including poxviruses. To determine the exposure of BCV following oral administration to prairie dogs, a pharmacokinetics (PK) study was performed. Analysis of BCV plasma concentrations indicated variability, conceivably due to the outbred nature of the animals. To determine BCV efficacy in the MPXV prairie dog model, groups of animals were intranasally challenged with 9 × 105 plaque-forming units (PFU; 90% lethal dose [LD90]) of MPXV on inoculation day 0 (ID0). Animals were divided into groups based on the first day of BCV treatment relative to inoculation day (ID-1, ID0, or ID1). A trend in efficacy was noted dependent upon treatment initiation (57% on ID-1, 43% on ID0, and 29% on ID1) but was lower than demonstrated in other animal models. Analysis of the PK data indicated that BCV plasma exposure (maximum concentration [Cmax]) and the time of the last quantifiable concentration (AUClast) were lower than in other animal models administered the same doses, indicating that suboptimal BCV exposure may explain the lower protective effect on survival.IMPORTANCE Preparedness activities against highly transmissible viruses with high mortality rates have been highlighted during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Smallpox, caused by variola virus (VARV) infection, is highly transmissible, with an estimated 30% mortality. Through an intensive vaccination campaign, smallpox was declared eradicated in 1980, and routine smallpox vaccination of individuals ceased. Today's current population has little/no immunity against VARV. If smallpox were to reemerge, the worldwide results would be devastating. Recent FDA approval of one smallpox antiviral (tecovirimat) was a successful step in biothreat preparedness; however, orthopoxviruses can become resistant to treatment, suggesting the need for multiple therapeutics. Our paper details the efficacy of the investigational smallpox drug brincidofovir in a monkeypox virus (MPXV) animal model. Since brincidofovir has not been tested in vivo against smallpox, studies with the related virus MPXV are critical in understanding whether it would be protective in the event of a smallpox outbreak.