AVE-8134(AVE-8134) - 药物靶点：PPARα_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

PPARα

作用机制

PPARα激动剂(过氧化物酶体增长因子活化受体α激动剂)

治疗领域

心血管疾病内分泌与代谢疾病

在研适应症-

非在研适应症

2型糖尿病心脏衰竭脂质代谢紊乱

原研机构

Sanofi

在研机构-

非在研机构

Sanofi

Genfit SA

Hoechst Pakistan Ltd.

最高研发阶段终止临床2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

分子式C22H23NO5

InChIKeyWLHOBCUVPMOXAT-UHFFFAOYSA-N

CAS号304025-09-0

关联

2

项与 AVE-8134 相关的临床试验

EUCTR2005-005141-19-IT / Not yet recruitingN/A

A 12-week, multicenter, double blind, placebo-controlled, randomized study of the efficacy and safety of 1.0 mg AVE8134 tablets for reducing A1c in the treatment of patients with confirmed type 2 diabetes mellitus who are not on current drug therapy - ND

开始日期2006-03-06

申办/合作机构

Sanofi-Synthélabo Ltd.

EUCTR2005-005141-19-DE / Not yet recruitingN/A

A 12-week, multicenter, double blind, placebo-controlled, randomized study of the efficacy and safety of 1.0 mg AVE8134 tablets for reducing A1c in the treatment of patients with confirmed type 2 diabetes mellitus who are not on current drug therapy

开始日期2006-01-30

申办/合作机构

Sanofi-Aventis Recherche et Développement SA

100 项与 AVE-8134 相关的临床结果

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100 项与 AVE-8134 相关的转化医学

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100 项与 AVE-8134 相关的专利（医药）

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3

项与 AVE-8134 相关的文献（医药）

2019-12-01·BMC Cancer2区 · 医学

PPARα ligand, AVE8134, and cyclooxygenase inhibitor therapy synergistically suppress lung cancer growth and metastasis

2区 · 医学

ArticleOA

作者: Wu, Lujin ; Dai, Meiyan ; Wang, Wei ; Chen, Chen ; Wang, Daowen ; Li, Huihui

AbstractBackgroundLung cancer (LC) is one of the leading causes of death worldwide, which highlights the urgent need for better therapies. Peroxisome proliferator-activated nuclear receptor alpha (PPARα), known as a key nuclear transcription factor involved in glucose and lipid metabolism, has been also implicated in endothelial proliferation and angiogenesis. However, the effects and potential mechanisms of the novel PPARα ligand, AVE8134, on LC growth and progression remain unclear.MethodsA subcutaneous tumour was established in mice by injecting TC-1 lung tumour cells (~ 1 × 106cells) into their shaved left flank. These mice were treated with three different PPARα ligands: AVE8134 (0.025% in drinking water), Wyeth-14,643 (0.025%), or Bezafibrate (0.3%). Tumour sizes and metastasis between treated and untreated mice were then compared by morphology and histology, and the metabolites of arachidonic acid (AA) were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Inhibition of either Cyp2c44 expression by genetic disruption or cyclooxygenase (COX) activity by indomethacin was used to test the mechanisms by which AVE8134 affects tumour growth.ResultsThe pharmacodynamics effects of AVE8134, Wyeth-14,643, and Bezafibrate on lipids control were similar. However, their effects on tumour suppression were different. Eicosanoid profile analysis showed that all PPARα ligands reduced the production of AA-derived epoxyeicosatrienoic acids (EETs) and increased the hydroxyl product, 11-hydroxyeicosatetraenoic acids (11-HETE). Moreover, increased 11-HETE promoted endothelial proliferation, angiogenesis, and subsequent tumour deterioration in a dose-dependent manner possibly via activating the AKT/extracellular signal-regulated kinase (ERK) pathway. The increased 11-HETE partly neutralized the benefits provided by the Cyp2c44-EETs system inhibited by PPARα ligands in tumour-bearing mice. AVE8134 treatment worsened the tumour phenotype in Cyp2c44 knockout mice, indicating that AVE8134 has contradictory effects on tumour growth. The COX inhibitor indomethacin strengthened the inhibitory actions of AVE8134 on tumour growth and metastasis by inhibiting the 11-HETE production in vivo and in vitro.ConclusionIn this study, we found that the degrees of inhibition on LC growth and metastasis by PPARα ligands depended on their bidirectional regulation on EETs and 11-HETE. Considering their safety and efficacy, the novel PPARα ligand, AVE8134, is a potentially ideal anti-angiogenesis drug for cancer treatment when jointly applied with the COX inhibitor indomethacin.

2012-01-01·Acta Pharmacologica Sinica1区 · 医学

AVE8134, a novel potent PPARα agonist, improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats

1区 · 医学

Article

作者: Wolfgang Linz ; Maike Glien ; Marcus Korn ; Heiner Glombik ; Eugen Falk ; Wolfgang Wendler ; Hans Ludwig Schäfer ; Andreas W Herling ; Hartmut Rütten

AIMAVE8134 is a structurally novel potent PPARα agonist. The aim of this study is to investigate the efficacy of AVE8134 on lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats.METHODSA cell based PPAR Gal4 transactivation assay was constructed for testing the activities of AVE8134 at 3 different PPAR isoforms in vitro. Transgenic human Apo A1 (hApo A1) mice and insulin-resistant ZDF rats were used to evaluate the effects of AVE8134 in vivo.RESULTSAVE8134 was a full PPARα dominated PPAR agonist (the values of EC(50) for human and rodent PPARα receptor were 0.01 and 0.3 μmol/L, respectively). AVE8134 was not active at PPARδ receptor. In female hApo A1 mice, AVE8134 (1-30 mg·kg(-1)·d(-1), po for 12 d) dose-dependently lowered the plasma triglycerides, and increased the serum HDL-cholesterol, hApo A1 and mouse Apo E levels. In female ZDF rats, AVE8134 (3-30 mg·kg(-1)·d(-1) for 2 weeks) improved insulin-sensitivity index. In pre-diabetic male ZDF rats (at the age of 7 weeks), AVE8134 (10 mg·kg(-1)·d(-1) for 8 weeks) produced an anti-diabetic action comparable to rosiglitazone, without the PPARγ mediated adverse effects on body weight and heart weight. In male ZDF rats (at the age of 6 weeks), AVE8134 (20 mg·kg(-1)·d(-1) for 12 weeks) increased mRNA levels of the target genes LPL and PDK4 about 20 fold in the liver, and there was no relevant effect with rosiglitazone.CONCLUSIONAVE8134 improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats.

2009-07-01·Acta Pharmacologica Sinica1区 · 医学

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats

1区 · 医学

Article

作者: Linz, Wolfgang ; Baader, Manuel ; Ruetten, Hartmut ; Kramer, Werner ; Falk, Eugen ; Schaefer, Hans-Ludwig ; Breitschopf, Kristin ; Wohlfart, Paulus ; Gerl, Martin

AIMTo investigate the efficacy of the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, AVE8134, in cellular and experimental models of cardiac dysfunction and heart failure.METHODSIn Sprague Dawley rats with permanent ligation of the left coronary artery (post-MI), AVE8134 was compared to the PPARgamma agonist rosiglitazone and in a second study to the ACE inhibitor ramipril. In DOCA-salt sensitive rats, efficacy of AVE8134 on cardiac hypertrophy and fibrosis was investigated. Finally, AVE8134 was administered to old spontaneously hypertensive rats (SHR) at a non-blood pressure lowering dose with survival as endpoint. In cellular models, we studied AVE8134 on hypertrophy in rat cardiomyocytes, nitric oxide signaling in human endothelial cells (HUVEC) and LDL-uptake in human MonoMac-6 cells.RESULTSIn post-MI rats, AVE8134 dose-dependently improved cardiac output, myocardial contractility and relaxation and reduced lung and left ventricular weight and fibrosis. In contrast, rosiglitazone exacerbated cardiac dysfunction. Treatment at AVE8134 decreased plasma proBNP and arginine and increased plasma citrulline and urinary NOx/creatinine ratio. In DOCA rats, AVE8134 prevented development of high blood pressure, myocardial hypertrophy and cardiac fibrosis, and ameliorated endothelial dysfunction. Compound treatment increased cardiac protein expression and phosphorylation of eNOS. In old SHR, treatment with a low dose of AVE8134 improved cardiac and vascular function and increased life expectancy without lowering blood pressure. AVE8134 reduced phenylephrine-induced hypertrophy in adult rat cardiomyocytes. In HUVEC, Ser-1177-eNOS phosphorylation but not eNOS expression was increased. In monocytes, AVE8134 increased the expression of CD36 and the macrophage scavenger receptor 1, resulting in enhanced uptake of oxidized LDL.CONCLUSIONThe PPARalpha agonist AVE8134 prevents post-MI myocardial hypertrophy, fibrosis and cardiac dysfunction. AVE8134 has beneficial effects against hypertension-induced organ damages, resulting in decreased mortality. The compound exerts its protective properties by a direct effect on cardiomyocyte hypertrophy, but also indirectly via monocyte signaling and increased endothelial NO production.Acta Pharmacologica Sinica (2009) 30: 935-946; doi: 10.1038/aps.2009.58; published online 8 June 2009.

100 项与 AVE-8134 相关的药物交易

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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
2型糖尿病	临床2期	西班牙	Sanofi	-
2型糖尿病	临床2期	德国	Sanofi	-
2型糖尿病	临床2期	意大利	Sanofi	-
2型糖尿病	临床2期	-	Genfit SA	-
心脏衰竭	临床2期	法国	Hoechst Pakistan Ltd.	-
心脏衰竭	临床2期	-	Genfit SA	-
心脏衰竭	临床2期	-	Sanofi	-
脂质代谢紊乱	临床2期	-	Sanofi	-
脂质代谢紊乱	临床2期	-	Genfit SA	-
脂质代谢紊乱	临床前	法国	Hoechst Pakistan Ltd.	-