Artefenomel
(Synonyms: OZ439) 目录号 : GC35399
An antimalarial agent
Cas No.:1029939-86-3
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
Artefenomel is an ozonide antimalarial agent.1 It is active against 3D7, Cam3.II, and Cam3.II_rev P. falciparum strains (LC50s = 8.7, 4.4, and 6.1 nM, respectively). Artefenomel reduces the number of trophozoites in P. falciparum-infected isolated human red blood cells (IC50 = 31 nM).2 In vivo, artefenomel (30 mg/kg) is 100% curative in a mouse model of P. berghei infection.3
1.Yang, T., Xie, S.C., Cao, P., et al.Comparison of the exposure time dependence of the activities of synthetic ozonide antimalarials and dihydroartemisinin against K13 wild-type and mutant Plasmodium falciparum strainsAntimicrob. Agents Chemother.60(8)4501-4510(2016) 2.Giannangelo, C., Stingelin, L., Yang, T., et al.Parasite-mediated degradation of synthetic ozonide antimalarials impacts in vitro antimalarial activityAntimicrob. Agents Chemother.62(3)e01566-e01617(2018) 3.Kim, H.S., Hammill, J.T., and Guy, R.K.Seeking the elusive long-acting ozonide: Discovery of artefenomel (OZ439)J. Med. Chem.60(7)2651-2653(2017)
| Cas No. | 1029939-86-3 | SDF | |
| 别名 | OZ439 | ||
| Canonical SMILES | [H][C@@]1(C[C@H](C2)C3)C4([C@@]3([H])C[C@H]2C1)O[C@]5(OO4)CC[C@H](CC5)C6=CC=C(C=C6)OCCN7CCOCC7 | ||
| 分子式 | C28H39NO5 | 分子量 | 469.61 |
| 溶解度 | DMSO: 4.2 mg/mL (8.94 mM) | 储存条件 | Store at -20°C, protect from light, stored under nitrogen |
| 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 | 2.1294 mL | 10.6471 mL | 21.2943 mL |
| 5 mM | 0.4259 mL | 2.1294 mL | 4.2589 mL |
| 10 mM | 0.2129 mL | 1.0647 mL | 2.1294 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。
Antimalarial Activity of Artefenomel Against Asexual Parasites and Transmissible Gametocytes During Experimental Blood-Stage Plasmodium vivax Infection
J Infect Dis 2022 Mar 15;225(6):1062-1069.PMID:32479608DOI:10.1093/infdis/jiaa287.
Background: Interventions that effectively target Plasmodium vivax are critical for the future control and elimination of malaria. We conducted a P. vivax volunteer infection study to characterize the antimalarial activity of Artefenomel, a new drug candidate. Methods: Eight healthy, malaria-naive participants were intravenously inoculated with blood-stage P. vivax and subsequently received a single oral 200-mg dose of Artefenomel. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma Artefenomel concentration. Mosquito feeding assays were conducted before Artefenomel dosing to investigate parasite transmissibility. Results: Initial parasite clearance occurred in all participants after Artefenomel administration (log10 parasite reduction ratio over 48 hours, 1.67; parasite clearance half-life, 8.67 hours). Recrudescence occurred in 7 participants 11-14 days after dosing. A minimum inhibitory concentration of 0.62 ng/mL and minimum parasiticidal concentration that achieves 90% of maximum effect of 0.83 ng/mL were estimated, and a single 300-mg dose was predicted to clear 109 parasites per milliliter with 95% certainty. Gametocytemia developed in all participants and was cleared 4-8 days after dosing. At peak gametocytemia, 75% of participants were infectious to mosquitoes. Conclusions: The in vivo antimalarial activity of Artefenomel supports its further clinical development as a treatment for P. vivax malaria. Clinical trials registration: NCT02573857.
Efficacy of OZ439 (Artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers
J Antimicrob Chemother 2016 Sep;71(9):2620-7.PMID:27272721DOI:10.1093/jac/dkw174.
Objectives: OZ439, or Artefenomel, is an investigational synthetic ozonide antimalarial with similar potency, but a significantly improved pharmacokinetic profile, compared with artemisinins. We wished to measure key pharmacokinetic and pharmacodynamic parameters and the pharmacokinetic/pharmacodynamic relationship of Artefenomel in humans to guide the drug's further development as combination therapy in patients. Patients and methods: We tested Artefenomel in the human induced blood-stage malaria (IBSM) model. Plasmodium infection was monitored by quantitative PCR (qPCR) and upon reaching 1000 parasites/mL single doses of 100, 200 and 500 mg of Artefenomel were administered orally with evaluation of drug exposure and parasitaemia until rescue treatment after 16 days or earlier, if required. Results: A single 100 mg dose had only a transient effect, while the 200 mg dose resulted in a significant reduction in parasitaemia before early recrudescence. At the highest (500 mg) dose, initial clearance of parasites below the limit of detection of qPCR was observed, with a 48 h parasite reduction ratio (PRR48) >10 000 and a parasite clearance half-life of 3.6 h (95% CI 3.4-3.8 h). However, at this dose, recrudescence was seen in four of eight subjects 6-10 days after treatment. Pharmacokinetic/pharmacodynamic modelling predicted an MIC of 4.1 ng/mL. Conclusions: These results confirm the antimalarial potential of Artefenomel for use in a single-exposure combination therapy. The observations from this study support and will assist further clinical development of Artefenomel.
Antimalarial activity of Artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial
Lancet Infect Dis 2016 Jan;16(1):61-69.PMID:26448141DOI:10.1016/S1473-3099(15)00320-5.
Background: Artefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of Artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria. Methods: This phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received Artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of Artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite reduction per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, number NCT01213966. Findings: Between Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of Artefenomel) but there were no further dropouts. The parasite reduction rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3-6·7) to 5·6 h (2·0-8·5) for P falciparum and 2·3 h (1·2-3·9) to 3·2 h (0·9-15·0) for P vivax. Maximum plasma concentrations, dose-proportional to 800 mg, occurred at 4 h (median). The estimated elimination half-life was 46-62 h. No serious drug-related adverse effects were reported; other adverse effects were generally mild and reversible, with the highest number in the 1200 mg cohort (17 [81%] patients with at least one adverse event). The most frequently reported adverse effect was an asymptomatic increase in plasma creatine phosphokinase concentration (200 mg, n=5; 400 mg, n=3; 800 mg, n=1; 1200 mg, n=3). Interpretation: Artefenomel is a new synthetic antimalarial peroxide with a good safety profile that clears parasitaemia rapidly in both P falciparum and P vivax malaria. Its long half-life suggests a possible use in a single-dose treatment in combination with other drugs. Funding: Bill & Melinda Gates Foundation, Wellcome Trust, and UK Department for International Development.
Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)
J Med Chem 2017 Apr 13;60(7):2654-2668.PMID:28052200DOI:10.1021/acs.jmedchem.6b01586.
Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide Artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addition of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, additional functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addition of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often associated with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.
Interactions of Artefenomel (OZ439) with Milk during Digestion: Insights into Digestion-Driven Solubilization and Polymorphic Transformations
Mol Pharm 2018 Aug 6;15(8):3535-3544.PMID:29932660DOI:10.1021/acs.molpharmaceut.8b00541.
Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and Artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To understand the role of milk digestion on the solubilization of OZ439 and polymorphism, we conducted real-time monitoring of crystalline drug in suspension during in vitro intestinal lipolysis of milk containing OZ439 using synchrotron X-ray scattering. OZ439 formed an unstable solid-state intermediate free base form (OZ439-FB form 1) at intestinal pH and was partially solubilized by milk fat globules prior to lipolysis. Dissolution of the free base form 1 and recrystallization of OZ439 in a more stable polymorphic form (OZ439-FB form 2) occurred during in vitro lipolysis in milk. Simply stirring the milk/drug suspension in the absence of lipase or addition of lipase to OZ439 in a lipid-free buffer did not induce this polymorphic transformation. The formation of OZ439-FB form 2 was therefore accelerated by the solubilization of OZ439-FB form 1 during the digestion of milk. Our findings confirmed that although crystalline precipitates of OZ439-FB form 2 could still be detected after in vitro digestion, milk-based lipid formulations provided a significant reduction in crystalline OZ439 compared to lipid-free formulations, which we attribute to the formation of colloidal structures by the digested milk lipids. Milk may therefore be particularly suited as a form of lipid-based formulation (LBF) for coadministration with OZ439, from which both an enhancement in OZ439 oral bioavailability and the delivery of essential nutrients should result.