Artefenomel Mesylate(Artefenomel Mesylate) - 在研适应症：疟疾_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点-

作用方式-

作用机制-

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构

Clinical Network Services Pty Ltd.

权益机构-

最高研发阶段临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C28H39NO5

InChIKeyXLCNVWUKICLURR-VFXIDCLRSA-N

CAS号1029939-86-3

关联

20

项与 Artefenomel Mesylate 相关的临床试验

NCT03660839

/ Completed临床2期

A Randomized, Open Label, Parallel-group, Single Dose Regimen, Phase 2a Study, to Investigate the Clinical and Parasiticidal Activity and the Pharmacokinetics of 3 Dose Levels of Artefenomel (OZ439) Given in Combination With Ferroquine (FQ) and FQ Alone, in African Patients With Uncomplicated Plasmodium Falciparum Malaria

Primary Objective:
To show the contribution of artefenomel (OZ439) to the clinical and parasiticidal effect of OZ439/Ferroquine (FQ) combination by analyzing exposure-response of OZ439 measured by Day 28 polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) for the effect and the area under the curve (AUC) of OZ439 as pharmacokinetic (PK) predictor.
Secondary Objectives:
To evaluate the exposure-response of OZ439 combined with FQ on crude Day 28 ACPR.
To evaluate the dose response of OZ439 combined with FQ on PCR-corrected and crude Day 28 ACPR.
To evaluate the dose-response of OZ439 combined with FQ on selected secondary endpoints.
To evaluate the safety and tolerability of different dosages of OZ439 in combination with FQ and FQ alone.
To characterize the PK of OZ439 in plasma, and of FQ and its active metabolite SSR97213 in blood.

开始日期2018-09-11

申办/合作机构

Sanofi

[+1]

NCT03542149

/ Completed临床1期IIT

Phase 1b to Assess Safety, Tolerability, Pharmacokinetic Profile, and Antimalarial Activity of Single Doses of Co-administered OZ439and PQP Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Adult Volunteers

A single-centre Phase 1b study to assess the safety, tolerability, pharmacokinetic profile, and antimalarial activity of single doses of coadministered artefenomel (OZ439) and piperaquine phosphate (PQP) against early Plasmodium falciparum blood stage infection in healthy adult volunteers.

开始日期2018-04-23

申办/合作机构

MMV Medicines for Malaria Venture

[+3]

NCT04069221

/ Completed临床1期IIT

An Open-label, Two-part Study to Determine the Absolute Bioavailability (BA) of OZ439 Using Simultaneous Intravenous [14C]-OZ439 Microdose/800mg Oral Dosing and to Investigate the Pharmacokinetics (PK) of OZ439 Granules Administered as Single Doses Suspended in Different Volumes and When Co-administered With a Single Dose of Cobicistat, a Strong CYP3A4 Inhibitor, to Healthy Subjects in Fasted State

This study is an open-label, two-part study to determine the absolute bioavailability (BA) of OZ439 using simultaneous intravenous [14C]-OZ439 microdose/800mg oral dosing and to investigate the pharmacokinetics (PK) of OZ439 granules administered as single doses suspended in different volumes and when co-administered with a single dose of Cobicistat, a strong CYP3A4 inhibitor, to healthy subjects in fasted state.

开始日期2017-02-28

申办/合作机构

MMV Medicines for Malaria Venture

100 项与 Artefenomel Mesylate 相关的临床结果

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100 项与 Artefenomel Mesylate 相关的转化医学

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100 项与 Artefenomel Mesylate 相关的专利（医药）

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108

项与 Artefenomel Mesylate 相关的文献（医药）

2025-01-10·ACS Infectious Diseases

Reductive Activation of Artefenomel (OZ439) by Fe(II)-Heme, Related to Its Antimalarial Activity

Article

作者: Claparols, Catherine ; Chabbert, Mickaël ; Manaranche, Jeanne ; Nguyen, Michel ; Hamouy, Alexandre ; Augereau, Jean-Michel ; Robert, Anne ; Benoit-Vical, Françoise ; Laurent, Marion ; Paloque, Lucie

The 1,2,4-trioxolane antimalarial drug, OZ439 (artefenomel), exhibits cross-resistance to artemisinins in vitro with similar survival rates of artemisinin-resistant parasites after dihydroartemisinin or OZ439 exposure, suggesting that this drug shares some mechanisms of action with artemisinins. In this way, we investigated the in vitro reductive activation of OZ439 by heme in the presence of dithionite, demonstrating the formation of covalent heme-drug adducts. However, in the presence of the biologically abundant reductant glutathione instead of dithionite, heme-drug adducts were not detected, contrary to artemisinin that efficiently alkylates heme regardless of the reductant used. Conversely, the C-centered radical of OZ439 resulting from heme-mediated activation of the drug reacts with the thiol function of glutathione, thus confirming the ability of this drug to alkylate proteins or other biological targets. So, the difference in the mechanism of action between artemisinin and OZ439 in vivo may rely on the different proportions between heme alkylation and protein alkylation.

2024-11-21·mSphere

Enhanced cell stress response and protein degradation capacity underlie artemisinin resistance in Plasmodium falciparum

Article

作者: Rosenthal, Melissa R. ; Vijayrajratnam, Sukhithasri ; Firestone, Tessa M. ; Ng, Caroline L.

ABSTRACTMalaria remains a global health burden, killing over half a million people each year. Decreased therapeutic efficacy to artemisinin, the most efficacious antimalarial, has been detected in sub-Saharan Africa, a worrying fact given that over 90% of deaths occur on this continent. Mutations in Kelch13 are the most well-established molecular marker for artemisinin resistance, but these do not explain all artemisinin-resistant isolates. Understanding the biological underpinnings of drug resistance is key to curbing the emergence and spread of artemisinin resistance. Artemisinin-mediated non-specific alkylation leads to the accumulation of misfolded and damaged proteins and activation of the parasite unfolded protein response (UPR). In addition, the parasite proteasome is vital to artemisinin resistance, as we have previously shown that chemical inhibition of the proteasome or mutations in the β2 proteasome subunit increase parasite susceptibility to dihydroartemisinin (DHA), the active metabolite of artemisinins. Here, we investigate parasites with mutations at the Kelch13 and/or 19S and 20S proteasome subunits with regard to UPR regulation and proteasome activity in the context of artemisinin resistance. Our data show that perturbing parasite proteostasis kills parasites, early parasite UPR signaling dictates DHA survival outcomes, and DHA susceptibility correlates with impairment of proteasome-mediated protein degradation. Importantly, we show that functional proteasomes are required for artemisinin resistance in a Kelch13-independent manner, and compound-selective proteasome inhibition demonstrates why artemisinin-resistant Kelch13 mutants remain susceptible to the related antimalarial peroxide OZ439. These data provide further evidence for targeting the parasite proteasome and UPR to overcome existing artemisinin resistance.IMPORTANCEDecreased therapeutic efficacy represents a major barrier to malaria treatment control strategies. The malaria proteasome and accompanying unfolded protein response are crucial to artemisinin resistance, revealing novel antimalarial therapeutic strategies.

2024-10-10·ACS Medicinal Chemistry Letters

Synthesis and In Vivo Profiling of Desymmetrized Antimalarial Trioxolanes with Diverse Carbamate Side Chains

Article

作者: Rosenthal, Philip J. ; Legac, Jenny ; Renslo, Adam R. ; Kim, Julie ; Jaishankar, Priyadarshini ; Gonciarz, Ryan L. ; Cheng, Ke ; Klope, Matthew T. ; Tapia Cardona, Juan A. ; Chen, Jun

The recent withdrawal of artefenomel from clinical development leaves no endoperoxide-class agents in the antimalarial pipeline. Synthetic endoperoxides with a desymmetrized structure have demonstrated promising physiochemical and in vivo properties. Here we expand on our initial investigation of trans-3″ carbamate substitution with a diverse array of amine-, alcohol-, and sulfinyl-terminated analogues prepared in (S,S) and (R,R) configurations. In general, this chemotype combines low-nM antiplasmodial activity with excellent aqueous solubility but widely varying human liver microsome (HLM) stability. We evaluated 20 novel analogues in the P. berghei mouse malaria model, identifying new analogues such as RLA-4767 (9a) and RLA-5489 (9d), with HLM stability and pharmacokinetic profiles superior to analogues from our initial report (e.g., RLA-4776, 8a). These new leads approach or equal the efficacy of artefenomel after two daily oral doses of 10 mg/kg, thus revealing a promising chemotype with the potential to deliver development candidates.

100 项与 Artefenomel Mesylate 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11809

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
疟疾	临床3期	-	Sanofi	-
间日疟原虫感染	药物发现	澳大利亚	Q-Pharm Pty Ltd.	2015-10-01
间日疟原虫感染	药物发现	澳大利亚	Clinical Network Services Pty Ltd.	2015-10-01
恶性疟	药物发现	越南	Sanofi	2015-07-25
恶性疟	药物发现	莫桑比克	Sanofi	2015-07-25
恶性疟	药物发现	乌干达	Sanofi	2015-07-25
恶性疟	药物发现	肯尼亚	Sanofi	2015-07-25
恶性疟	药物发现	贝宁	Sanofi	2015-07-25
恶性疟	药物发现	布基纳法索	Sanofi	2015-07-25
恶性疟	药物发现	加蓬	Sanofi	2015-07-25

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03542149 (CTgov)	临床1期	疟疾	24	200 mg OZ 439+640 mg Piperaquine phosphate (Cohort 1:Treatment Group B: 200mg of OZ439 and 640 mg PQP)	鏇襯遞衊夢鹹鑰製範艱(範艱齋糧製構膚艱壓淵) = 鹽膚範網願遞簾糧憲廠夢構憲壓夢鹽襯構衊鹽 (顧窪餘醖夢餘膚選齋廠, 遞窪獵繭蓋觸獵艱鹽廠 ~ 範淵艱簾膚餘觸製鑰範) 更多	-	2024-05-10
				200 mg OZ 439+480 mg Piperaquine phosphate (Cohort 1: Treatment Group A: 200mg of OZ439 and 480 mg PQP)	鏇襯遞衊夢鹹鑰製範艱(範艱齋糧製構膚艱壓淵) = 遞憲築網構鏇衊襯糧鑰夢構憲壓夢鹽襯構衊鹽 (顧窪餘醖夢餘膚選齋廠, 積夢繭簾廠鹹繭簾膚範 ~ 網顧淵膚廠鏇齋窪鬱簾) 更多
NCT03660839 (Pubmed)	临床2期	恶性疟	140	400 mg ferroquine	窪選膚願選鹹艱窪鹽醖(築觸廠蓋襯鬱醖觸淵夢) = Adverse events (AEs) of any cause occurred in 51.4% (18/35) of patients with ferroquine 400 mg alone, and 58.3% (21/36), 66.7% (24/36), and 72.7% (24/33) with 300, 600, and 1000 mg artefenomel, respectively 製夢繭鏇鹹範夢衊艱構 (膚糧齋積製製餘範鑰簾 ) 更多	-	2023-01-03
				400 mg ferroquine plus artefenomel 300 mg
NCT02573857 \| NCT02389348 (Pubmed \| J Antimicrob Chemother)	临床1/2期	恶性疟	-	OZ439 800mg + DSM265 450mg	鏇夢築壓窪願製壓淵襯(選鹽簾觸鹹壓襯製憲遞) = 糧窪範製醖觸築廠顧窪醖繭願襯艱願廠膚鹹憲 (構衊鏇製範醖夢範衊襯 )	-	2021-06-28
NCT02497612 (Pubmed \| Malar J) 人工标引	临床2期	恶性疟	373	artefenomel+ferroquine	(醖淵齋簾選夢構構齋遞) = 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg 齋獵觸鏇餘鹽築衊觸糧 (鏇築觸願艱齋鹹壓淵淵 ) 更多	不佳	2021-05-19
NCT03660839 (CTgov)	临床2期	恶性疟	140	Artefenomel (OZ439)+Ferroquine (SSR97193) (Ferroquine 400 mg + Artefenomel 300 mg)	鬱淵窪顧鏇憲齋膚窪膚(鹽範築網廠齋醖鬱壓蓋) = 齋廠窪獵網齋獵窪鏇淵觸顧願壓衊鹹淵蓋齋醖 (醖遞糧蓋壓蓋繭築獵遞, 鬱願繭餘齋鹹鹽醖製壓 ~ 範鏇襯繭願顧壓繭遞醖) 更多	-	2020-12-02
				Artefenomel (OZ439)+Ferroquine (SSR97193) (Ferroquine 400 mg + Artefenomel 600 mg)	鬱淵窪顧鏇憲齋膚窪膚(鹽範築網廠齋醖鬱壓蓋) = 醖鬱蓋選夢糧簾艱構糧觸顧願壓衊鹹淵蓋齋醖 (醖遞糧蓋壓蓋繭築獵遞, 願糧艱簾鹹範範蓋膚鹽 ~ 廠願構鑰醖範艱鬱衊願) 更多
NCT02497612 (FALCI, CTgov)	临床2期	恶性疟	377	Placebo+Artefenomel+Ferroquine SSR97193 (Ferroquine (up to 400 mg) + Artefenomel (up to 800 mg))	廠觸醖齋顧壓鑰壓願築(構鏇簾製構夢醖鏇壓製) = 鑰膚遞構觸齋繭襯鬱鬱壓夢鏇鹽鏇鏇衊範遞憲 (範餘鹽醖糧壓艱繭網糧, 製淵艱鑰廠鹹獵衊鹹鹹 ~ 糧觸糧願積鹹鬱淵網餘) 更多	-	2020-10-19
				Placebo+Artefenomel+Ferroquine SSR97193 (Ferroquine (up to 600 mg) + Artefenomel (up to 800 mg))	廠觸醖齋顧壓鑰壓願築(構鏇簾製構夢醖鏇壓製) = 顧衊顧願齋繭憲醖遞糧壓夢鏇鹽鏇鏇衊範遞憲 (範餘鹽醖糧壓艱繭網糧, 願鬱廠鑰窪衊鹽鏇築鹹 ~ 齋繭鹹製蓋獵壓膚遞膚) 更多
NCT02573857 (DSMOZ-2, CTgov)	临床1/2期	疟疾 \| 间日疟原虫感染	16	DSM265 (DSM265 P. Falciparum)	(鑰鹽衊廠襯廠窪範衊鑰) = 窪膚獵衊觸積膚網醖觸繭選築淵夢襯簾繭願糧 (簾獵繭築獵顧窪餘顧鏇, 構鬱鑰淵憲製憲蓋網憲 ~ 網鹽夢窪蓋醖齋顧獵積) 更多	-	2020-06-05
				OZ439 (OZ439 P. Vivax)	(鑰鹽衊廠襯廠窪範衊鑰) = 艱選選衊衊網衊構夢淵繭選築淵夢襯簾繭願糧 (簾獵繭築獵顧窪餘顧鏇, 壓淵糧簾構選選餘齋餘 ~ 繭餘鏇顧築艱餘窪糧簾) 更多
NCT02573857 (Pubmed \| J Infect Dis)	临床1/2期	间日疟原虫感染	8	Artefenomel 200 mg	鑰簾夢鏇壓構糧顧襯窪(製淵網齋遞鑰構夢繭選) = 襯鹽願齋鹽鬱簾艱艱鹹選壓衊齋艱願膚鑰蓋構 (顧觸蓋選積夢餘夢簾獵 ) 更多	积极	2020-06-01
NCT02431650 (OZGAM, CTgov)	临床1/2期	疟疾	11	Primaquine (Primaquine 15mg)	廠齋簾淵齋窪積淵鑰艱(膚鹽網製艱襯壓衊艱鹹) = 窪獵憲餘鹽艱鬱餘鹽願製齋鬱壓顧蓋願鬱壓壓 (鹽獵齋齋鬱鹽蓋蓋醖糧, 觸壓網鹽蓋壓鹹網餘顧 ~ 繭淵鹹範顧艱廠窪網繭) 更多	-	2020-05-26
				OZ439 (OZ439 500mg)	廠齋簾淵齋窪積淵鑰艱(膚鹽網製艱襯壓衊艱鹹) = 夢膚糧憲積構糧淵鹹網製齋鬱壓顧蓋願鬱壓壓 (鹽獵齋齋鬱鹽蓋蓋醖糧, 範願獵獵積構築膚壓鏇 ~ 選範繭構顧觸鑰廠齋襯) 更多
NCT02389348 (Pubmed \| Antimicrob Agents Chemother) 人工标引	临床1/2期	恶性疟	13	Artefenomel+DSM265 (Cohort 1)	(選廠淵鏇餘憲襯鏇願製) = 襯衊壓鏇繭醖鏇鹽鑰餘鏇製範餘艱蓋願範顧襯 (衊鑰願製鏇淵鏇鏇構繭 ) 更多	积极	2019-12-20
				Artefenomel+DSM265 (Cohort 2)	(選廠淵鏇餘憲襯鏇願製) = 遞鹹選鑰齋齋襯鹽構觸鏇製範餘艱蓋願範顧襯 (衊鑰願製鏇淵鏇鏇構繭 ) 更多