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索伐曲肽介导的内皮素 B 受体激动作用与神经紊乱的抑制。

Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders.

机构信息

Pharmaceutical Science, Chicago College of Pharmacy Downers Grove, Midwestern University, Downers Grove, IL 60515, USA.

Pharmazz Inc. Research and Development, Willowbrook, IL 60527, USA.

出版信息

Int J Mol Sci. 2022 Mar 15;23(6):3146. doi: 10.3390/ijms23063146.


DOI:10.3390/ijms23063146
PMID:35328566
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8955091/
Abstract

Neurological/neurovascular disorders constitute the leading cause of disability and the second leading cause of death globally. Major neurological/neurovascular disorders or diseases include cerebral stroke, Alzheimer's disease, spinal cord injury, neonatal hypoxic-ischemic encephalopathy, and others. Their pathophysiology is considered highly complex and is the main obstacle in developing any drugs for these diseases. In this review, we have described the endothelin system, its involvement in neurovascular disorders, the importance of endothelin B receptors (ETBRs) as a novel potential drug target, and its agonism by IRL-1620 (INN-sovateltide), which we are developing as a drug candidate for treating the above-mentioned neurological disorders/diseases. In addition, we have highlighted the results of our preclinical and clinical studies related to these diseases. The phase I safety and tolerability study of sovateltide has shown it as a safe and tolerable compound at therapeutic dosages. Furthermore, preclinical and clinical phase II studies have demonstrated the efficacy of sovateltide in treating acute ischemic stroke. It is under development as a first-in-class drug. In addition, efficacy studies in Alzheimer's disease (AD), acute spinal cord injury, and neonatal hypoxic-ischemic encephalopathy (HIE) are ongoing. Successful completion of these studies will validate that ETBRs signaling can be an important target in developing drugs to treat neurological/neurovascular diseases.

摘要

神经系统/血管疾病是全球范围内导致残疾和死亡的主要原因。主要的神经系统/血管疾病包括中风、阿尔茨海默病、脊髓损伤、新生儿缺氧缺血性脑病等。其病理生理学被认为非常复杂,是开发这些疾病药物的主要障碍。在这篇综述中,我们描述了内皮素系统,它在神经血管疾病中的作用,内皮素 B 受体 (ETBR) 作为一个新的潜在药物靶点的重要性,以及我们正在开发的 IRL-1620(INN-sovateltide)对其的激动作用,该药物被开发为治疗上述神经疾病的候选药物。此外,我们还强调了与这些疾病相关的临床前和临床研究结果。sovateltide 的 I 期安全性和耐受性研究表明,它在治疗剂量下是一种安全且耐受良好的化合物。此外,临床前和临床 II 期研究表明,sovateltide 在治疗急性缺血性中风方面具有疗效。它正在开发作为一种首创药物。此外,在阿尔茨海默病 (AD)、急性脊髓损伤和新生儿缺氧缺血性脑病 (HIE) 中正在进行疗效研究。这些研究的成功完成将验证 ETBR 信号可以成为开发治疗神经血管疾病药物的重要靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da6d/8955091/31add7b2199c/ijms-23-03146-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da6d/8955091/68d18da960d5/ijms-23-03146-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da6d/8955091/31add7b2199c/ijms-23-03146-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da6d/8955091/68d18da960d5/ijms-23-03146-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da6d/8955091/31add7b2199c/ijms-23-03146-g002.jpg

相似文献

[1]
Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders.

Int J Mol Sci. 2022-3-15

[2]
Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke.

CNS Drugs. 2021-1

[3]
Sovateltide (IRL-1620) affects neuronal progenitors and prevents cerebral tissue damage after ischemic stroke.

Can J Physiol Pharmacol. 2020-9

[4]
Neuroprotective Effect of Sovateltide (IRL 1620, PMZ 1620) in a Neonatal Rat Model of Hypoxic-Ischemic Encephalopathy.

Neuroscience. 2022-1-1

[5]
Sovateltide: First Approval.

Drugs. 2023-9

[6]
Advances in Therapies to Treat Neonatal Hypoxic-Ischemic Encephalopathy.

J Clin Med. 2023-10-20

[7]
Stimulation of endothelin B receptors by IRL-1620 decreases the progression of Alzheimer's disease.

Neuroscience. 2015-8-20

[8]
Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke.

Sci Rep. 2020-7-29

[9]
Oxidative stress: A target to treat Alzheimer's disease and stroke.

Neurochem Int. 2023-5

[10]
Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats.

Brain Res. 2011-9-7

引用本文的文献

[1]
Efficacy and Safety of Sovateltide in Patients with Acute Cerebral Ischaemic Stroke: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase III Clinical Trial.

Drugs. 2024-12

[2]
Structure of endothelin ET receptor-G complex in a conformation stabilized by unique NPxxL motif.

Commun Biol. 2024-10-16

[3]
Current and future strategies for targeting the endothelin pathway in cardiovascular disease.

Nat Cardiovasc Res. 2023-11

[4]
Sovateltide (ILR-1620) Improves Motor Function and Reduces Hyperalgesia in a Rat Model of Spinal Cord Injury.

Neurocrit Care. 2024-10

[5]
Advances in Therapies to Treat Neonatal Hypoxic-Ischemic Encephalopathy.

J Clin Med. 2023-10-20

[6]
Alzheimer's Disease: Novel Targets and Investigational Drugs for Disease Modification.

Drugs. 2023-10

[7]
Structural insights into endothelin receptor signalling.

J Biochem. 2023-9-29

[8]
Sovateltide: First Approval.

Drugs. 2023-9

[9]
Characterization of age- and stage-dependent impaired adult subventricular neurogenesis in 5XFAD mouse model of Alzheimer's disease.

BMB Rep. 2023-9

[10]
Cryo-EM structure of the endothelin-1-ET-G complex.

Elife. 2023-4-25

本文引用的文献

[1]
A Middle Ground for Accelerated Drug Approval-Lessons From Aducanumab.

JAMA. 2021-10-12

[2]
An Appropriate Use of Accelerated Approval - Aducanumab for Alzheimer's Disease.

N Engl J Med. 2021-8-26

[3]
Revisiting FDA Approval of Aducanumab.

N Engl J Med. 2021-8-26

[4]
Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke.

CNS Drugs. 2021-1

[5]
Sovateltide (IRL-1620) activates neuronal differentiation and prevents mitochondrial dysfunction in adult mammalian brains following stroke.

Sci Rep. 2020-7-29

[6]
Sovateltide (IRL-1620) affects neuronal progenitors and prevents cerebral tissue damage after ischemic stroke.

Can J Physiol Pharmacol. 2020-9

[7]
2020 Alzheimer's disease facts and figures.

Alzheimers Dement. 2020-3-10

[8]
Discovery of endogenous inverse agonists for G protein-coupled receptor 6.

Biochem Biophys Res Commun. 2019-12-7

[9]
Endothelin: 30 Years From Discovery to Therapy.

Hypertension. 2019-11-4

[10]
The neuropathological diagnosis of Alzheimer's disease.

Mol Neurodegener. 2019-8-2

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