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(+)-SJ733 (SJ000557733) Sale

(Synonyms: SJ000557733) 目录号 : GC32130

(+)-SJ733 (SJ000557733) 是一种抗疟疾药物,还可以抑制 Na+-ATPase PfATP4。

(+)-SJ733 (SJ000557733) Chemical Structure

Cas No.:1424799-20-1

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10mM (in 1mL DMSO)
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1mg
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5mg
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10mg
¥8,836.00
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50mg
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100mg
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment:

10 mL of asynchronous culture suspensions (2% hematocrit), at different parasite densities (104, 105, 106, 107, and 108 parasites), are added to each well of a 6-well plate. (+)-SJ733 is added to each well to make a final compound concentration of 1.8 μM, corresponding to 30×EC50 of the compound. Three wells are used for each parasite density. Plates are incubated at 37° C under an atmosphere of 90% N2, 5% O2, 5% CO2 for 90 days under constant drug pressure. The media of each well is replaced 3 times a week with freshly made media containing a compound concentration of 30×EC50. In addition, each well is split (1:2) once a week. Parasite outgrowth is monitored 3 times a week by transferring quadruplicate 40 μL aliquots from each well into a 384-well assay plate and determining parasitemia by a previously described method[1].

Animal experiment:

The pharmacokinetics of (+)-SJ733 are studied in overnight-fasted male Sprague Dawley rats weighing 267 to 291 g predose. Rats have access to water ad libitum throughout the pre- and post-dose sampling period, and access to food is reinstated 4 h post-dose. (+)-SJ733 is administered intravenously as a 10 min constant rate infusion (1.0 mL per rat, n=3 rats) and orally by gavage (10 mL/kg, n=3 rats). The IV formulation consists of pH 7.4 isotonic phosphate buffered saline containing 1% (w/v) hydroxypropyl-β-cyclodextrin, 10% (v/v) ethanol, 10% (v/v) propylene glycol and 40% (v/v) PEG400 whereas the oral formulation is an aqueous suspension in 0.5% (w/v) hydroxypropyl methylcellulose, 0.5% (v/v) benzyl alcohol and 0.4% (v/v) Tween80. Aliquots of the formulations are retained for analysis of the actual dose administered. Samples of arterial blood and total urine are collected at various time points up to 24 h post-dose[1].

References:

[1]. Jiménez-Díaz MB, et al. (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5455-62.

产品描述

(+)-SJ733 is a clinical candidate for malaria which can also inhibit Na+-ATPase PfATP4.

(+)-SJ733 binds to a single receptor site in P. falciparum-infected erythrocytes with equivalent affinity to its growth-inhibitory potency (kd=50 nM). (+)-SJ733 has not exhibited either significant safety liabilities at any dose in extensive profiling in vitro or significant safety or tolerability liabilities in either single- or repeat-dose studies at any dose tested in any preclinical species (no observed adverse effect level and maximum tolerated dose >240 mg/kg from 7-d repeat dosing study in rat). Therefore, (+)-SJ733 is expected to have a safety margin of at least 43-fold[1].

Treatment of P. falciparum-infected NOD-scid IL2Rγnull mice with (+)-SJ733 causes rapid clearance of parasites, which are 80% depleted within the first 24 h and undetectable by 48 h. (+)-SJ733 is highly potent and efficacious against P. falciparum 3D70087/N9 in vivo when administered as four sequential daily oral doses in the NOD-scid IL2Rγnull mouse model, with a 90% effective dose, (ED90 1.9 mg/kg) and exposure [area under the curve at ED90 (AUCED90), 1.5 μM?h] superior to artesunate (11.1 mg/kg; AUCED90 not determined), chloroquine (4.3 mg/kg; AUCED90 3.1 μM?h), and pyrimethamine (0.9 mg/kg; AUCED90 5. μM?h) in the same model. When treated with the ED90 dose, (+)-SJ733 concentrations in blood remain above the average in vitro EC90 for 6 to 10 h after each dose[1].

[1]. Jiménez-Díaz MB, et al. (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5455-62.

Chemical Properties

Cas No. 1424799-20-1 SDF
别名 SJ000557733
Canonical SMILES O=C([C@@H](C1=C2C=CC=C1)[C@@H](C3=CC=CN=C3)N(CC(F)(F)F)C2=O)NC4=CC=C(F)C(C#N)=C4
分子式 C24H16F4N4O2 分子量 468.4
溶解度 DMSO : 50 mg/mL (106.75 mM) 储存条件 Store at -20°C
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溶解性数据

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1 mg 5 mg 10 mg
1 mM 2.1349 mL 10.6746 mL 21.3493 mL
5 mM 0.427 mL 2.1349 mL 4.2699 mL
10 mM 0.2135 mL 1.0675 mL 2.1349 mL
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Research Update

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Proc Natl Acad Sci U S A.2014 Dec 16;111(50):E5455-62.PMID:25453091DOI: 10.1073/pnas.1414221111.

Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na(+) levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na(+) homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.

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.

Reduced deformability of parasitized red blood cells as a biomarker for anti-malarial drug efficacy

Malar J.2015 Oct 31;14:428.PMID:26520795DOI: 10.1186/s12936-015-0957-z.

Background: Malaria remains a challenging and fatal infectious disease in developing nations and the urgency for the development of new drugs is even greater due to the rapid spread of anti-malarial drug resistance. While numerous parasite genetic, protein and metabolite biomarkers have been proposed for testing emerging anti-malarial compounds, they do not universally correspond with drug efficacy. The biophysical character of parasitized cells is a compelling alternative to these conventional biomarkers because parasitized erythrocytes become specifically rigidified and this effect is potentiated by anti-malarial compounds, such as chloroquine and artesunate. This biophysical biomarker is particularly relevant because of the mechanistic link between cell deformability and enhanced splenic clearance of parasitized erythrocytes. Methods: Recently a microfluidic mechanism, called the multiplexed fluidic plunger that provides sensitive and rapid measurement of single red blood cell deformability was developed. Here it was systematically used to evaluate the deformability changes of late-stage trophozoite-infected red blood cells (iRBCs) after treatment with established clinical and pre-clinical anti-malarial compounds. Results: It was found that rapid and specific iRBC rigidification was a universal outcome of all but one of these drug treatments. The greatest change in iRBC rigidity was observed for (+)-SJ733 and NITD246 spiroindolone compounds, which target the Plasmodium falciparum cation-transporting ATPase ATP4. As a proof-of-principle, compounds of the bisindole alkaloid class were screened, where cladoniamide A was identified based on rigidification of iRBCs and was found to have previously unreported anti-malarial activity with an IC50 lower than chloroquine. Conclusion: These results demonstrate that rigidification of iRBCs may be used as a biomarker for anti-malarial drug efficacy, as well as for new drug screening. The novel anti-malarial properties of cladoniamide A were revealed in a proof-of-principle drug screen.