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DDD107498

现货
Catalog No.
A8711
新型的多级抗疟疾制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 4,000.00
Ship with 10-15 days

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Background

DDD107498 is a potent and novel multiple-stage antimalarial agent against multiple life-cycle stages of the Plasmodium parasite. [1]
DDD107498 has an acceptable safety profile and good pharmacokinetic properties. Translation elongation factor 2 (eEF2) has been identified as the molecular target of DDD107498. The factor eEF2 is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. [1]
DDD107498 showed excellent activity against Plasmodium falciparum 3D7 parasites with EC50 value of 1.0 nM, EC90 value of 2.4 nM and EC99 value of 5.9 nM. Furthermore, DDD107498 was more potent than artesunate in ex vivo assays against a range of clinical isolates of both P. falciparum (median EC50 = 0.81 nM (range 0.29–3.29 nM), n = 44) and P. vivax (median EC50 = 0.51 nM (range 0.25–1.39 nM), n = 28) collected from patients with malaria from southern Papua. [1]
DDD107498 showed an EC50 < 1 nM against the liver schizont forms of P. berghei and Plasmodium yoelii. DDD107498 potently inhibited both male and female gamete formation from the gametocyte stage at similar concentrations [1.8 nM (95% CI 1.6–2.1 nM) and 1.2 nM (95% CI 0.8–1.6 nM)] respectively. DDD107498 blocked subsequent oocyst development in the mosquito after 7 days with an EC50 of 1.8 nM. [1]
DDD107498 had a 90% reduction in parasitaemia (ED90) of 0.57 mg/kg after a single oral dose in mice infected with the rodent parasite Plasmodium berghei. When orally dosed daily for 4 days, the ED90 on day 7 after infection was 0.95 mg/kg/day. Blood sampling from the infected SCID (severe combined immunodeficiency) mice suggested a minimum parasiticidal concentration for DDD107498 of 10–13 ng/ml for asexual blood-stage infections. [1]
In contrast, the compound was not toxic to human cells (MRC5 and Hep-G2 cells) at much higher concentrations (>20,000-fold selectivity). DDD107498 displayed excellent pharmacokinetic properties in preclinical species, including good oral bioavailability and long plasma half-life. DDD107498 showed good drug-like properties including metabolic stability when incubated with hepatic microsomes or hepatocytes from several species; good solubility in a range of different media; and low protein binding. [1]
Reference:
1.Baragaña B, Hallyburton I, Lee MC et al. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature. 2015 Jun 18;522(7556):315-20.

文献引用

1. Christine Moore Sheridan."Probing Translational Regulation by the Malaria Parasite Plasmodium falciparum: Applying a Novel In Vitro Assay to Identify Genetic Determinants of Regulation and Identify Small Molecules Exploiting P. falciparum Translation as a Drug Target."University of California.2019.
2. Christine Moore Sheridan, Valentina E. Garcia, et al. "The Plasmodium falciparum cytoplasmic translation apparatus: a promising therapeutic target not yet exploited by clinically approved antimalarials." bioRxiv. 2018 September 12.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt462.56
Cas No.1469439-69-7
FormulaC27H31FN4O2
Solubility≥14.05mg/mL in DMSO
Chemical Name6-fluoro-2-(4-(morpholinomethyl)phenyl)-N-(2-(pyrrolidin-1-yl)ethyl)quinoline-4-carboxamide
SDFDownload SDF
Canonical SMILESO=C(NCCN1CCCC1)C2=CC(C3=CC=C(CN4CCOCC4)C=C3)=NC5=CC=C(F)C=C52
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

抗疟疾试验 [1]:

疟疾寄生虫

各种疟疾寄生虫

制备方法

该化合物可溶于DMSO。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

0.0001 ~ 10 μM

实验结果

DDD107498显著抑制3D7寄生虫,其EC50值为1.0 nM。DDD107498对几种耐药菌株也表现出类似的抑制作用。此外,相对于青蒿琥酯,DDD107498对临床样品中的恶性疟原虫和间日疟原虫显示出较高的抑制作用,其EC50值分别为0.81 nM和0.51 nM。此外,在较高浓度下,DDD107498对人MRC5和Hep-G2细胞无毒性。

动物实验 [1]:

动物模型

携带人类红细胞并感染了恶性疟原虫菌株3D70087/N9的NOD-scid IL-2R_null小鼠

给药剂量

0.1、0.3、0.6、1或3 mg/kg/day;口服给药;持续4天

实验结果

在携带人类红细胞并感染了恶性疟原虫菌株3D70087/N9的NOD-scid IL-2R_null小鼠中,每天口服给予DDD107498,持续4天。于感染后第7天,ED90值为0.95 mg/kg/day。受感染SCID小鼠的血液样品显示,DDD107498对无性血液感染期的最低杀虫浓度为10 ~ 13 ng/mL。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Baragaa B, Hallyburton I, Lee MC et al. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature. 2015 Jun 18;522(7556):315-20.

质量控制

质量控制和MSDS

批次:

化学结构

DDD107498

相关生物数据

DDD107498

相关生物数据

DDD107498