AVE-0657(AVE-0657) - 药物靶点：NHE3_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

NHE3

作用机制

NHE3抑制剂(钠氢交换蛋白-3抑制剂)

治疗领域

神经系统疾病心血管疾病呼吸系统疾病

在研适应症-

非在研适应症

Cheyne-Stokes呼吸心脏衰竭阻塞性睡眠呼吸暂停低通气综合征

原研机构

Sanofi

在研机构-

非在研机构

Sanofi

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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关联

3

项与 AVE-0657 相关的临床试验

NCT00694720 / Terminated临床2期

A Double-Blind, Randomized, Placebo-Controlled, Study Evaluating the Safety and Activity of Four Escalating Single Doses of AVE0657 in Congestive Heart Failure Patients Presenting as Cheyne-Stokes Breathing Syndrome

The primary objective of this study is to assess the activity on breathing parameters of 4 escalating doses of AVE0657 in comparison to placebo in patients with Cheynes-Stokes Breathing Syndrome.

开始日期2008-06-01

申办/合作机构

Sanofi

EUCTR2007-002172-34-DE / Not yet recruitingN/A

A double-blind, randomized, placebo-controlled, study evaluating the safety and activity of four escalating single doses of AVE0657 in congestive heart failure patients presenting as Cheyne-Stokes Breathing Syndrome

开始日期2008-01-04

申办/合作机构

Sanofi-Aventis Recherche et Développement SA

NCT00614250 / Completed临床2期

A Double-blind, Randomized, Placebo-controlled, Study of the Safety and Activity of Four Escalating Single Doses of AVE0657 in Patients Suffering From Obstructive Sleep Apnea Hypopnea Syndrome

The primary objective of this study is to assess the activity of 4 escalating doses of AVE0657 in comparison to placebo in patients with Obstructive Sleep Apnea Hypopnea Syndrome.

开始日期2008-01-01

申办/合作机构

Sanofi

100 项与 AVE-0657 相关的临床结果

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100 项与 AVE-0657 相关的转化医学

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100 项与 AVE-0657 相关的专利（医药）

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4

项与 AVE-0657 相关的文献（医药）

2021-06-01·Current Hypertension Reports2区 · 医学

New Insights into the Critical Importance of Intratubular Na+/H+ Exchanger 3 and Its Potential Therapeutic Implications in Hypertension

2区 · 医学

Review

作者: Soleimani, Manoocher ; Li, Xiao Chun ; Zhuo, Jia Long

PURPOSE OF REVIEWThe sodium (Na⁺) and hydrogen (H⁺) exchanger 3 (NHE3), known as solute carrier family 9 member 3 (SLC9A3), mediates active transcellular Na⁺ and bicarbonate reabsorption in the small intestine of the gut and proximal tubules of the kidney. The purpose of this article is to review and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure (BP) homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension.RECENT FINDINGSRecently, our and other laboratories have generated or used novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal BP homeostasis and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The new findings demonstrate that NHE3 contributes to about 10 to 15 mmHg to basal blood pressure levels, and that deletion of NHE3 at the whole-kidney or proximal tubule level, or pharmacological inhibition of NHE3 at the kidney level with an orally absorbable NHE3 inhibitor AVE-0657, attenuates ~ 50% of Ang II-induced hypertension in mice. The results support the proof-of-concept hypothesis that NHE3 plays critical roles in physiologically maintaining normal BP and in the development of Ang II-dependent hypertension. Our results also strongly suggest that NHE3 in the proximal tubules of the kidney may be therapeutically targeted to treat poorly controlled hypertension in humans.

2019-09-01·Hypertension

Proximal Tubule-Specific Deletion of the NHE3 (Na ⁺ /H ⁺ Exchanger 3) in the Kidney Attenuates Ang II (Angiotensin II)-Induced Hypertension in Mice

Article

作者: Zheng, Xiaowen ; Chen, Xu ; Tauc, Michel ; Zhuo, Jia L. ; Zhu, Dongmin ; Li, Xiao C. ; Zhou, Xinchun ; Zhao, Chunling ; Rubera, Isabelle ; Zhang, Jianfeng ; Soleimani, Manoocher

The present study directly tested the hypothesis that the NHE3 (Na + /H + exchanger 3) in the proximal tubules of the kidney is required for the development of Ang II (angiotensin II)-induced hypertension using PT- Nhe3−/− (proximal tubule-specific NHE3 knockout) mice. Specifically, PT- Nhe3−/− mice were generated using the SGLT2-Cre / Nhe3loxlox approach, whereas Ang II-induced hypertension was studied in 12 groups (n=5–12 per group) of adult male and female wild-type (WT) and PT- Nhe3−/− mice. Under basal conditions, systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were significantly lower in male and female PT- Nhe3−/− than WT mice ( P <0.01). A high pressor, 1.5 mg/kg per day, intraperitoneal or a slow pressor dose of Ang II, 0.5 mg/kg per day, intraperitoneal for 2 weeks significantly increased systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure in male and female WT mice ( P <0.01), but the hypertensive response to Ang II was markedly attenuated in male and female PT- Nhe3−/− mice ( P <0.01). Ang II impaired the pressure-natriuresis response in WT mice, whereas proximal tubule-specific deletion of NHE3 improved the pressure-natriuresis response in Ang II-infused PT- Nhe3−/− mice ( P <0.01). AT 1 receptor blocker losartan completely blocked Ang II-induced hypertension in both WT and PT- Nhe3−/− mice ( P <0.01). However, inhibition of nitric oxide synthase with L-N G -Nitroarginine methyl ester had no effect on Ang II-induced hypertension in WT or PT- Nhe3−/− mice (not significant). Furthermore, Ang II-induced hypertension was significantly attenuated by an orally absorbable NHE3 inhibitor AVE0657. In conclusion, NHE3 in the proximal tubules of the kidney may be a therapeutical target in hypertension induced by Ang II or with increased NHE3 expression in the proximal tubules.

2014-02-01·Neuroscience Bulletin2区 · 医学

Blockade of Na+/H+ exchanger type 3 causes intracellular acidification and hyperexcitability via inhibition of pH-sensitive K+ channels in chemosensitive respiratory neurons of the dorsal vagal nucleus in rats

2区 · 医学

Article

作者: Wang, Guang-Fa ; Zhang, Jing ; Ma, Jing ; Wang, Ke-Wei ; Veasey, Sigrid C. ; Peng, Hui

Extracellular pH (pHe) and intracellular pH (pHi) are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na(+)/H(+) exchanger 3 (NHE-3), a key pHi regulator in the brainstem, decreases the pHi, leading to membrane depolarization for the maintenance of respiration. However, how intracellular pH affects the neuronal excitability of respiratory neurons remains largely unknown. In this study, we showed that NHE-3 mRNA is widely distributed in respiration-related neurons of the rat brainstem, including the dorsal vagal nucleus (DVN). Whole-cell patch clamp recordings from DVN neurons in brain slices revealed that the standing outward current (Iso) through pH-sensitive K(+) channels was inhibited in the presence of the specific NHE-3 inhibitor AVE0657 that decreased the pHi. Exposure of DVN neurons to an acidified pHe and AVE0657 (5 μmol/L) resulted in a stronger effect on firing rate and Iso than acidified pHe alone. Taken together, our results showed that intracellular acidification by blocking NHE-3 results in inhibition of a pH-sensitive K(+) current, leading to synergistic excitation of chemosensitive DVN neurons for the regulation of respiration.

100 项与 AVE-0657 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
Cheyne-Stokes呼吸	临床2期	德国	Sanofi	2008-06-01
Cheyne-Stokes呼吸	临床2期	法国	Sanofi	2008-06-01
Cheyne-Stokes呼吸	临床2期	西班牙	Sanofi	2008-06-01
心脏衰竭	临床2期	法国	Sanofi	2008-06-01
心脏衰竭	临床2期	德国	Sanofi	2008-06-01
心脏衰竭	临床2期	西班牙	Sanofi	2008-06-01
阻塞性睡眠呼吸暂停低通气综合征	临床2期	德国	Sanofi	2008-01-01
阻塞性睡眠呼吸暂停低通气综合征	临床2期	法国	Sanofi	2008-01-01
阻塞性睡眠呼吸暂停低通气综合征	临床2期	西班牙	Sanofi	2008-01-01