Cipargamin (NITD609)
(Synonyms: (1'R,3'S)-5,7'-二氯-6'-氟-2',3',4',9'-四氢-3'-甲基螺[3H-吲哚-3,1'-[1H]吡啶并[3,4-B]吲哚]-2(1H)-酮,NITD609; KAE609) 目录号 : GC33919
An antimalarial agent
Cas No.:1193314-23-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cipargamin is an antimalarial agent.1,2,3 It inhibits the Na+-ATPase activity of wild-type or mutant P. falciparum P-type ATPase (PfATP4; IC50s = 12.3-13.9 and 21.1-32.5 nM, respectively, in P. falciparum membranes).1 Cipargamin is active against the P. falciparum chloroquine-sensitive strain NF54 and chloroquine-resistant strain K1 (IC50s = 0.5 and 0.6 nM, respectively).2 It reduces parasitemia and increases survival in a mouse model of P. berghei infection when administered at doses of 10, 30, and 100 mg/kg.3
1.Rosling, J.E.O., Ridgway, M.C., Summers, R.L., et al.Biochemical characterization and chemical inhibition of PfATP4-associated Na+-ATPase activity in Plasmodium falciparum membranesJ. Biol. Chem.293(34)13327-13337(2018) 2.van Pelt-Koops, J.C., Pett, H.E., Graumans, W., et al.The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to Anopheles mosquito vectorAntimicrob. Agents Chemother.56(7)3544-3548(2012) 3.Rottmann, M., McNamara, C., Yeung, B.K.S., et al.Spiroindolones, a potent compound class for the treatment of malariaScience329(5996)1175-1180(2010)
| Cas No. | 1193314-23-6 | SDF | |
| 别名 | (1'R,3'S)-5,7'-二氯-6'-氟-2',3',4',9'-四氢-3'-甲基螺[3H-吲哚-3,1'-[1H]吡啶并[3,4-B]吲哚]-2(1H)-酮,NITD609; KAE609 | ||
| Canonical SMILES | FC1=C(Cl)C=C(NC2=C3C[C@H](C)N[C@@]2(C4=C(C=CC(Cl)=C4)N5)C5=O)C3=C1 | ||
| 分子式 | C19H14Cl2FN3O | 分子量 | 390.24 |
| 溶解度 | DMSO : 50 mg/mL (128.13 mM);Water : < 0.1 mg/mL (insoluble) | 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 | 2.5625 mL | 12.8126 mL | 25.6253 mL |
| 5 mM | 0.5125 mL | 2.5625 mL | 5.1251 mL |
| 10 mM | 0.2563 mL | 1.2813 mL | 2.5625 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。
The early preclinical and clinical development of Cipargamin (KAE609), a novel antimalarial compound
Travel Med Infect Dis 2020 Jul-Aug;36:101765.PMID:32561392DOI:10.1016/j.tmaid.2020.101765.
Background: Cipargamin (KAE609) is a novel spiroindolone class drug for the treatment of malaria, currently undergoing phase 2 clinical development. This review provides an overview and interpretation of the pre-clinical and clinical data of this possible next-generation antimalarial drug published to date. Methods: We systematically searched the literature for studies on the preclinical and clinical development of Cipargamin. PubMed and Google Scholar databases were searched using the terms 'Cipargamin', 'KAE609' or 'NITD609' in the English language; one additional article was identified during revision. Nineteen of these in total 43 papers identified reported original studies; 13 of those articles were on pre-clinical studies and 6 reported clinical trials. Results: A total of 20 studies addressing its preclinical and clinical development have been published on this compound at the time of writing. Cipargamin acts on the PfATP4, which is a P-type Na + ATPase disrupting the Na + homeostasis in the parasite. Cipargamin is a very fast-acting antimalarial, it is active against all intra-erythrocytic stages of the malaria parasite and exerts gametocytocidal activity, with transmission-blocking potential. It is currently undergoing phase 2 clinical trial to assess safety and efficacy, with a special focus on hepatic safety. Conclusion: In the search for novel antimalarial drugs, Cipargamin exhibits promising properties, exerting activity against multiple intra-erythrocytic stages of plasmodia, including gametocytes. It exhibits a favourable pharmacokinetic profile, possibly allowing for single-dose treatment with a suitable combination partner. According to the clinical results of the first studies in Asian malaria patients, a possible safety concern is hepatotoxicity.
Spiroindolone NITD609 is a novel antimalarial drug that targets the P-type ATPase PfATP4
Future Med Chem 2016;8(2):227-38.PMID:26824174DOI:10.4155/fmc.15.177.
Malaria is caused by the Plasmodium parasite and is a major health problem leading to many deaths worldwide. Lack of a vaccine and increasing drug resistance highlights the need for new antimalarial drugs with novel targets. Antiplasmodial activity of spiroindolones was discovered through whole-cell, phenotypic screening methods. Optimization of the lead spiroindolone improved both potency and pharmacokinetic properties leading to drug candidate NITD609 which has produced encouraging results in clinical trials. Spiroindolones inhibit PfATP4, a P-type Na(+)-ATPase in the plasma membrane of the parasite, causing a fatal disruption of its sodium homeostasis. Other diverse compounds from the Malaria Box appear to target PfATP4 warranting further research into its structure and binding with NITD609 and other potential antimalarial drugs.
Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria
Clin Infect Dis 2022 May 30;74(10):1831-1839.PMID:34410358DOI:10.1093/cid/ciab716.
Background: Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of Cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of Cipargamin (hepatic safety data are reported elsewhere). Methods: This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. Results: All single or multiple Cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each Cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. Conclusions: Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. Clinical trials registration: ClinicalTrials.gov (NCT03334747).
Defining the Antimalarial Activity of Cipargamin in Healthy Volunteers Experimentally Infected with Blood-Stage Plasmodium falciparum
Antimicrob Agents Chemother 2021 Jan 20;65(2):e01423-20.PMID:33199389DOI:10.1128/AAC.01423-20.
The spiroindolone Cipargamin, a new antimalarial compound that inhibits Plasmodium ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of Cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum Eight subjects were intravenously inoculated with parasite-infected erythrocytes and received a single oral dose of 10 mg Cipargamin 7 days later. Blood samples were collected to monitor the development and clearance of parasitemia and plasma Cipargamin concentrations. Parasite regrowth was treated with piperaquine monotherapy to clear asexual parasites, while allowing gametocyte transmissibility to mosquitoes to be investigated. An initial rapid decrease in parasitemia occurred in all participants following Cipargamin dosing, with a parasite clearance half-life of 3.99 h. As anticipated from the dose selected, parasite regrowth occurred in all 8 subjects 3 to 8 days after dosing and allowed the pharmacokinetic/pharmacodynamic relationship to be determined. Based on the limited data from the single subtherapeutic dose cohort, a MIC of 11.6 ng/ml and minimum parasiticidal concentration that achieves 90% of maximum effect of 23.5 ng/ml were estimated, and a single 95-mg dose (95% confidence interval [CI], 50 to 270) was predicted to clear 109 parasites/ml. Low gametocyte densities were detected in all subjects following piperaquine treatment, which did not transmit to mosquitoes. Serious adverse liver function changes were observed in three subjects, which led to premature study termination. The antimalarial activity characterized in this study supports the further clinical development of Cipargamin as a new treatment for P. falciparum malaria, although the hepatic safety profile of the compound warrants further evaluation. (This study has been registered at ClinicalTrials.gov under identifier NCT02543086.).
A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to Cipargamin
Nat Commun 2022 Sep 30;13(1):5746.PMID:36180431DOI:10.1038/s41467-022-33403-9.
Diverse compounds target the Plasmodium falciparum Na+ pump PfATP4, with Cipargamin and (+)-SJ733 the most clinically-advanced. In a recent clinical trial for Cipargamin, recrudescent parasites emerged, with most having a G358S mutation in PfATP4. Here, we show that PfATP4G358S parasites can withstand micromolar concentrations of Cipargamin and (+)-SJ733, while remaining susceptible to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation in Toxoplasma gondii ATP4, decrease the sensitivity of ATP4 to inhibition by Cipargamin and (+)-SJ733, thereby protecting parasites from disruption of Na+ regulation. The G358S mutation reduces the affinity of PfATP4 for Na+ and is associated with an increase in the parasite's resting cytosolic [Na+]. However, no defect in parasite growth or transmissibility is observed. Our findings suggest that PfATP4 inhibitors in clinical development should be tested against PfATP4G358S parasites, and that their combination with unrelated antimalarials may mitigate against resistance development.