阿曲留通(Atreleuton) - 药物靶点：5-LOX_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Atreleuton (USAN/INN)、A 85761、A-85761

+ [5]

靶点

5-LOX

作用机制

5-LOX抑制剂(5-脂氧合酶抑制剂)

治疗领域

免疫系统疾病呼吸系统疾病神经系统疾病+ [2]

在研适应症-

非在研适应症

急性冠状动脉综合征哮喘动脉粥样硬化+ [4]

原研机构

Abbott Laboratories

在研机构-

非在研机构

VIA Pharmaceuticals, Inc.Tallikut Pharmaceuticals, Inc.

Madrigal Pharmaceuticals, Inc.

+ [1]

最高研发阶段终止临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C16H15FN2O2S

InChIKeyMMSNEKOTSJRTRI-LLVKDONJSA-N

CAS号154355-76-7

关联

3

项与阿曲留通相关的临床试验

NCT00552188 / Completed临床2期

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of the Effect of VIA-2291, a 5-Lipoxygenase Inhibitor, on Vascular Inflammation in Patients After an Acute Coronary Syndrome Event

The purpose of this study is to determine the effect of VIA-2291 as compared to placebo on vascular inflammation following 24 weeks of dosing.

开始日期2007-10-01

申办/合作机构

Tallikut Pharmaceuticals, Inc.

[+5]

NCT00352417 / Completed临床2期

A Phase 2 Randomized, Double-blind, Placebo-controlled Study of the Effects of VIA-2291, a 5-Lipoxygenase Inhibitor, on Atherosclerotic Plaque and Biomarkers of Vascular Inflammation in Patients With Carotid Stenosis Undergoing Elective Carotid Endarterectomy

This is a study to compare the effect of VIA-2291 vs. Placebo on various inflammatory biomarkers in patients with carotid stenosis scheduled for elective carotid endarterectomy

开始日期2006-07-01

申办/合作机构

Tallikut Pharmaceuticals, Inc.

NCT00358826 / Completed临床2期

Clinical Study Protocol No. VIA-2291-01, A Phase 2 Randomized, Double-blind, Parallel-group, Placebo-controlled, Dose-ranging Study of the Effect of VIA-2291 on Vascular Inflammation in Patients After an Acute Coronary Syndrome Event

This is a dose ranging study to compare the effect of VIA-2291 vs. Placebo on various inflammatory biomarkers in patients with recent acute coronary events

开始日期2006-07-01

申办/合作机构

Tallikut Pharmaceuticals, Inc.

[+1]

100 项与阿曲留通相关的临床结果

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100 项与阿曲留通相关的转化医学

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100 项与阿曲留通相关的专利（医药）

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26

项与阿曲留通相关的文献（医药）

2023-03-01·Cardiology in review4区 · 医学

Anti-inflammatory Therapeutics and Coronary Artery Disease

4区 · 医学

Review

作者: Roy, Sion K. ; Eghtedari, Bibinaz ; Budoff, Matthew J.

It has been demonstrated that atherosclerotic disease progression is contingent upon chronic inflammation. The sequence of events leading up to plaque formation, instability, and eventual plaque rupture hinges upon the interaction of proinflammatory cytokines and fat deposition within the coronary vasculature. Over the past decade, a large body of evidence has demonstrated the efficacy of specific anti-inflammatory therapeutics in halting the progression of coronary artery disease. Despite this, these therapeutics have yet to be included in guideline-directed medical therapy regimens. This review will focus on several anti-inflammatories, which have been studied in the context of cardiovascular disease—colchicine, canakinumab, VIA-2291, and methotrexate, and will highlight the potential benefits majority hold in hindering atherosclerosis and cardiovascular disease progression. This holds especially true for individuals already on optimal medical therapy who continue to be at high risk for adverse cardiovascular events.

2022-06-01·BMJ open

Examining anti-inflammatory therapies in the prevention of cardiovascular events: protocol for a systematic review and network meta-analysis of randomised controlled trials

Article

作者: Geejo, Aishwarya ; Shin, Sheojung ; Pearson, Alexander Liam ; Wells, George A ; Beanlands, Rob ; Fehlmann, Christophe A ; Visintini, Sarah ; Shahab, Saba ; Bezzina, Kathryn A ; Boczar, Kevin Emery

Introduction:

Inflammation is emerging as an important risk factor for atherosclerotic cardiovascular disease and has been a recent target for many novel therapeutic agents. However, comparative evidence regarding efficacy of these anti-inflammatory treatment options is currently lacking.

Methods and analysis:

This systematic review will include randomised controlled trials evaluating the effect of anti-inflammatory agents on cardiovascular outcomes in patients with known cardiovascular disease. Studies will be retrieved from Medline, Embase, the Cochrane Central Register of Controlled Trials, as well as clinical trial registry websites, Europe PMC and conference abstract handsearching. No publication date or language restrictions will be imposed. Eligible interventions must have some component of anti-inflammatory agent. These include (but are not limited to): non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, prednisone, methotrexate, canakinumab, pexelizumab, anakinra, succinobucol, losmapimod, inclacumab, atreleuton, LP-PLA2(darapladib) and sPLA2(varespladib). The primary outcomes will include major adverse cardiac events (MACE), and each individual component of MACE (myocardial infarction, stroke and cardiovascular death). Key secondary outcomes will include unstable angina, heart failure, all-cause mortality, cardiac arrest and revascularisation. Screening, inclusion, data extraction and quality assessment will be performed independently by two reviewers. Network meta-analysis based on the random effects model will be conducted to compare treatment effects both directly and indirectly. The quality of the evidence will be assessed with appropriate tools including the Grading of Recommendations, Assessment, Development and Evaluation profiler or Confidence in Network Meta-Analysis tool.

Ethics and dissemination:

Ethics approval is not required for this systematic review. The findings will be disseminated through a peer-reviewed journal.

PROSPERO registration number:

CRD42022303289.

2021-12-01·Cytokine & growth factor reviews2区 · 医学

The role and transformative potential of IL-19 in atherosclerosis

2区 · 医学

Review

作者: Dongming Xing ; Xinlin Liu ; Wujun Chen ; Shuai Wang ; Jiyao Xing

Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Traditionally, IL-19 was thought to be expressed in only immune cells, but studies revealed that IL-19 is also expressed in multiple atherosclerotic plaque cell types, but not normal arteries, in humans and mice. IL-19 reduces the development of atherosclerosis via multiple mechanisms, including balancing cholesterol metabolism; enhancing Th2 immune cell polarization; reducing the inflammatory response; and reducing the proliferation, migration and chemotaxis of vascular smooth muscle cells (VSMCs). Clinical and/or animal studies have primarily aimed to achieve regression and/or stabilization of atherosclerotic plaques, with regression in particular indicating a very good drug response. Most antiatherosclerotic drugs in current clinical use, including atorvastatin and alirocumab, target hyperlipidemia. Several other drugs have also been investigated in clinical trials as anti-inflammatory agents; the development of some of these agents has been terminated (canakinumab, darapladib, varespladib, losmapimod, atreleuton, setileuton, PF-04191834, veliﬂapon, and methotrexate), but others remain in development (ziltivekimab, tocilizumab, Somalix, IFM-2427, anakinra, mesenchymal stem cells (MSCs), colchicine, everolimus, allopurinol, and montelukast). Most of the tested drugs have shown a limited ability to reverse atherosclerosis in animal studies. Interestingly, recombinant IL-19 (rIL-19) was shown to reduce atherosclerosis development in a time- and dose-dependent manner. A low dose of rIL-19 (1 ng/g/day) reduced aortic arch and root plaque areas by 70.1% and 32.1%, respectively, in LDLR^-/- mice. At 10 ng/g/day, rIL-19 completely eliminated atherosclerotic plaques. There were no sex differences in the effects of rIL-19 on atherosclerotic mice. Thus, low-dose rIL-19 is an effective antiatherosclerotic agent, in addition to its efficacy in intimal hyperplasia, spinal cord injury, stroke, and multiple sclerosis. We propose that IL-19 is a promising biomarker and target for the diagnosis and treatment of atherosclerosis. This review considers the role and mechanism of action of IL-19 in atherosclerosis and discusses whether IL-19 is a potential therapeutic target for this condition.

1

项与阿曲留通相关的新闻（医药）

2023-09-10

·CPHI制药在线

5-脂氧合酶及其抑制剂研究进展

关注并星标CPHI制药在线脂氧合酶是一类非血红素含铁双加氧酶，存在于动、植物的组织和细胞中，可催化花生四烯（AA）、二十二碳六烯酸和各种多不饱和脂肪酸(polyunsaturated fatty acid，PUFA)的氧化反应。脂氧合酶主要分为1、3、5、8、12、15-脂氧合酶6种亚型。其中5-脂氧合酶(5-lipoxygenase，5-LOX)是脂氧合酶同工酶中最常见的、研究较为深入的非血红素铁蛋白氧化代谢酶，是许多高活性氧化脂质生物合成中的关键酶。5-LOX作用于AA氧化通过两步完成：第一步使5-LOX氧化成5-羟过氧化二十碳四烯酸（5-HPETE）再转化为5-羟基二十碳四烯酸（5-HETE）。第二步催化5-HPETE生成白三烯A4(leukotriene A4，LTA 4 )。LTA 4既可转化为致炎物白三烯B4(leukotriene B4，LTB4)，也可生成白三烯C4(leukotriene C4，LTC4)进而生成白三烯D4(leukotriene D4，LTD4)、白三烯E4(leukotrieneE4，LTE4)等导致过敏反应的反应物质。白三烯物质（LT）是哮喘、慢性阻塞性肺疾病、炎症性肠病、关节炎、动脉粥样硬化、皮炎和癌症等多种慢性炎症性疾病相关的促炎性脂质介质，通过进一步的双加氧作用和对外源化学物的协同氧化作用，在炎症、哮喘、脑缺血、部分恶性肿瘤及阿尔茨海默症等疾病的发生和发展中具有极其重要的作用。5-LOX抑制剂通过阻断LT的产生，抑制AA转变为LT，从而减少炎症的产生。因此，开发有效的5-LOX抑制剂对治疗上述疾病至关重要。根据抑制剂的作用机制可将5-LOX抑制剂分为直接抑制剂和间接抑制剂。直接抑制剂直接抑制剂主要针对5-LOX分子结构特点进行研发，比如干扰5-LOX C-端催化结构域中Fe2+与Fe3+正常的转换，或者是与铁离子络合来抑制5-LOX的活性。直接抑制剂包括氧化还原抑制剂、非氧化还原抑制剂、铁离子配体抑制剂。间接抑制剂主要是围绕FLAP进行设计，在5-LOX途径中需要FLAP的参与，抑制了FLAP 就能阻断 5-LOX 途径。 1、氧化还原抑制剂氧化还原抑制剂一般是亲脂性的小分子芳香族化合物，例如酚类化合物和醌类化合物。1,4-苯醌AA-861是第一批氧化还原型5-LOX抑制剂，经多项研究证实其在体内可产生抗炎作用，并已经通过了预防季节性过敏性鼻炎的临床试验。苯醌衍生物在人类单核细胞、中性粒细胞和整个人类血液中可作为5-LOX的有效活性抑制剂，对两种LT相关炎症标准化动物模型的实验研究表明，新型1,4-苯醌RF-Id能够通过抑制LT的产生，在体内抑制导致抗炎反应的5-LOX。此外，氧化还原抑制剂还包括去甲二氢愈创木酸 (NDGA)、香豆素、黄酮类化合物等几类物质，它们均在体外实验证实具有高效的5-LOX 抑制作用。氧化还原抑制剂能把Fe3+还原为Fe2+，从而干扰了铁离子的正常催化循环，阻止5-LOX 的激活，导致5-LOX途径不能正常进行。此外，黄酮类的某些化合物，例如槲皮素、芦丁由于B环上具有邻位的酚羟基，他们还能与Fe3+络合，从而加大了对 5-LOX 的抑制作用。另外，研究人员用荧光法测定了氧化还原抑制剂的氧化还原电势，并揭示了氧化还原抑制剂的作用机制，当氧化还原抑制剂存在时，它降低了Fe2+与Fe3+之间的转换，抑制了酶催化反应，从而需要更多的脂质过氧化物去氧化Fe2+转变成 Fe3+，因此，在酶催化反应过程中，真正参与催化反应的脂质过氧化物的量是很少的，酶催化反应即被抑制。 2、非氧化还原抑制剂非氧化还原抑制剂属于竞争型抑制剂，它能与底物AA竞争结合到5-LOX 的活性中心，导致5-LOX途径受阻，相对于其他抑制剂具有更高的选择性，但是磷酸化作用和Ca2+会干扰这些抑制剂。ZD2138 和ZM230487属于非氧化还原抑制剂中的两个代表。它们属于甲氧基四氢吡喃衍生物，临床研究表明，ZD2138 能够有效抑制关节炎和哮喘病。实验研究表明，一些天然产物和ZD2138 的杂交体 L-697198，以及通过对L-697198结构进行优化而得到的L-708780和L-739010，表现出良好的生物利用度。但后续动物实验发现，该种抑制剂有多种毒性，限制了它的临床使用。此外，L-739,010、CJ-13,610和PF-419183也是非氧化还原型5-LOX抑制剂，在细胞测定中显示IC50的低纳摩尔范围。L-739,010可以减少LT介导的炎症反应，且其抗痛觉亢进活性与炎症大脑中LT水平降低有关，在急性卡拉胶模型和慢性炎症模型中表现出优异的药效和药代动力学，但难以形成共价蛋白结合代谢物。CJ-13,610在大鼠内侧半月板横切面模型上对骨关节炎疼痛有抑制作用，口服CJ-13,610可逆转该动物模型的两种疼痛模式，包括触觉异位痛和负重差异。通过大鼠气囊模型证明了PF-4191834对LTB4产生的抑制作用，PF-4191834也完成了哮喘的Ⅱ期临床试验，但其用于膝骨关节炎的Ⅱ期临床试验因出现晕厥、急性肝炎和胃溃疡出血等严重不良事件而被终止。 3、铁离子配体抑制剂铁离子配体抑制剂大体包括两种，异羟基肟酸类和羟基脲类，羟肟酸衍生物BWA4C和羟基脲衍生物Zileuton是有效的口服5-LOX抑制剂。BWA4C是溃疡性结肠炎患结肠组织中LTB4合成的有效选择性抑制剂，以BWA4C为代表的乙酰异羟肟酸5-脂氧合酶抑制剂有助于评价LTB4在溃疡性结肠炎中的临床意义，并为该病的治疗提供新的途径。Zileuton使急性和慢性气道功能得到了改善，也减少了β受体激动剂或糖皮质激素的需求，并在美国被批准用于治疗哮喘，但是对于变应性鼻炎、类风湿关节炎和炎症性肠病的治疗潜力较低，并且它有许多缺点，如肝毒性和不良药代动力学特征等。以Zileuton结构为基础设计出了一种新型抑制剂VIA-2291，可以在支气管痉挛动物模型中表现出比Zileuton高5倍的效力，口服半衰期16 h，对哮喘患者的运动性支气管收缩有一定的疗效。VIA-2291已成功完成动脉粥样硬化和心血管疾病的Ⅱ期临床试验，成为临床开发中领先的5-LOX抑制剂之一。RBX-7796是一种具有十二烷基链的尿素衍生物，可抑制大鼠血液中LTB4的体外合成，并对各种炎症和支气管收缩动物模型有活性。间接抑制剂间接抑制剂不直接抑制5-LOX的活性。FLAP是5-LOX 激活蛋白，它能结合底物 AA 并且把它转移给5-LOX。在细胞中，5-LOX 与 FLAP 是共同表达的。当给予足够的底物 AA，如果缺少FLAP，细胞也不能合成白三烯等物质。MK886 是研发出来的第一代间接抑制剂，同时也是第一个用于临床的间接抑制剂。它能与AA竞争FLAP 上的结合位点，导致5-LOX 无法与FLAP 相互结合，5-LOX 途径因此受阻。此外，抑制剂AM803正在进行临床实验，并已经完成了对哮喘病人的二期阶段试验，它的衍生物AM103也成功通过了一期临床实验。不过研发的某些抑制剂也存在问题，如NGDA和MK0591 等也存在两方面的缺陷，一是不能特异性针对5-LOX，对人体正常的代谢也有一定的干扰，从而限制了临床应用；二是稳定性不够，直接影响抑制剂的抑制效力。参考资料 [1]李丹凤,范涛,鹿欣雨.5-脂氧合酶抑制剂的研究进展[J].生命的化学,2023,43(05):666-673. [2]黄凯,蒋世云,陈柳军.5-脂氧合酶及其抑制剂[J].中国生物化学与分子生物学报,2014,30(12):1190-1196. 作者简介：小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床1期核酸药物

100 项与阿曲留通相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D03010	-	-	DB12758

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
哮喘	临床3期	日本	-	-
哮喘	临床3期	-	Abbott Laboratories	-
哮喘	临床3期	-	Madrigal Pharmaceuticals, Inc.	-
颈动脉狭窄	临床2期	意大利	Tallikut Pharmaceuticals, Inc.	2006-07-01
冠心病	临床2期	美国	Tallikut Pharmaceuticals, Inc.	2006-07-01
冠心病	临床2期	加拿大	Tallikut Pharmaceuticals, Inc.	2006-07-01
动脉粥样硬化斑块	临床2期	意大利	Tallikut Pharmaceuticals, Inc.	2006-07-01
血管炎	临床2期	美国	Tallikut Pharmaceuticals, Inc.	2006-07-01
血管炎	临床2期	加拿大	Tallikut Pharmaceuticals, Inc.	2006-07-01
血管炎	临床2期	意大利	Tallikut Pharmaceuticals, Inc.	2006-07-01

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临床结果

适应症

分期

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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


NCT00358826 (VIA-2291-01, Pubmed \| Clin Cardiol)	临床2期	疾病进展	54	VIA-2291 25mg	繭襯蓋夢網築襯範膚夢(憲鹽製憲襯夢鑰構鏇顧) = 廠鏇齋簾網糧觸鏇淵範鹽廠選齋願憲廠壓餘襯 (獵積繭構願築構構糧齋 ) 更多	-	2017-04-01
				VIA-2291 50mg	繭襯蓋夢網築襯範膚夢(憲鹽製憲襯夢鑰構鏇顧) = 鬱繭鬱願構窪壓選選蓋鹽廠選齋願憲廠壓餘襯 (獵積繭構願築構構糧齋 ) 更多
NCT00552188 (Pubmed \| Atherosclerosis) 人工标引	临床2期	急性冠状动脉综合征 \| 血管炎	52	VIA-2291	壓選鬱憲憲範廠襯遞範(窪鬱鹽壓淵齋廠淵鬱鹽) = 鏇鑰願觸製積網範憲壓鹹膚憲簾蓋襯繭醖襯壓 (壓淵廠築構遞膚鹽鹹觸 )	积极	2015-05-01
				Placebo	-
NCT00552188 (CTgov)	临床2期	急性冠状动脉综合征 \| 血管炎	52	VIA-2291 (VIA-2291)	膚鏇醖範製願餘範獵觸(鹽構糧艱糧鑰憲廠憲齋) = 構鹹觸簾夢鏇醖窪淵膚選鹹窪醖蓋遞獵廠願糧 (淵艱築簾積製範鹹衊夢, 構鬱糧醖鹽顧艱觸築顧 ~ 鏇餘築餘蓋憲壓範獵淵) 更多	-	2013-08-09
				Placebo (Placebo)	膚鏇醖範製願餘範獵觸(鹽構糧艱糧鑰憲廠憲齋) = 鬱夢鹽廠鹽製憲鏇鏇衊選鹹窪醖蓋遞獵廠願糧 (淵艱築簾積製範鹹衊夢, 廠壓鬱鹹衊齋築餘積獵 ~ 鏇夢繭鬱鹽遞願鹹襯繭) 更多
NCT00358826 (VIA-2291-01, CTgov)	临床2期	急性冠状动脉综合征 \| 冠心病 \| 血管炎	191	VIA-2291 (VIA-2291 25 mg)	蓋築醖積衊遞繭鹹餘淵(廠鬱築憲鹹遞鬱願鏇淵) = 憲顧遞鬱選鬱構衊夢夢膚遞窪選淵蓋願夢膚糧 (壓鏇鑰積顧壓鑰壓夢壓, 膚鑰鬱醖蓋夢齋網艱餘 ~ 範簾範網願夢餘廠觸簾) 更多	-	2012-07-23
				VIA-2291 (VIA-2291 50 mg)	蓋築醖積衊遞繭鹹餘淵(廠鬱築憲鹹遞鬱願鏇淵) = 積襯築繭遞夢窪簾觸範膚遞窪選淵蓋願夢膚糧 (壓鏇鑰積顧壓鑰壓夢壓, 蓋壓衊遞築憲艱選夢鏇 ~ 壓鹽襯鬱鑰淵衊壓衊窪) 更多
NCT00352417 (CTgov)	临床2期	动脉粥样硬化 \| 血管炎 \| 动脉粥样硬化斑块 ... 更多	50	VIA-2291	糧壓糧簾鬱觸窪憲鏇餘(糧憲鬱鏇艱遞壓鏇獵淵) = 廠憲艱廠範築構範遞餘網夢積糧艱顧齋膚觸鹽 (糧醖蓋鏇衊鏇廠窪鹽積, 選鑰製膚願簾繭獵衊衊 ~ 願遞衊選顧鏇積壓鹹鑰) 更多	-	2012-07-20