The Current Landscape in the Development of Small-molecule Modulators Targeting Sphingosine-1-phosphate Receptors to Treat Neurodegenerative Diseases

IF 2.9 4区医学 Q3 CHEMISTRY, MEDICINAL

Current topics in medicinal chemistry Pub Date : 2024-04-27 DOI:10.2174/0115680266288509240422112839

Sidharth Sankar Kar, Soumya Ranjan Gharai, Sujit Kumar Sahu, V. Ravichandiran, Sharada Prasanna Swain

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引用次数: 0

Abstract

: Sphingosine 1-phosphate (S1P) is extensively researched as a lysophospholipid and is crucial in various physiological and pathological processes. It achieves this via signalling through five different subtypes of G protein-coupled receptors (GPCRs), namely S1PR1 to S1PR5. S1PR modulators possess the ability to traverse the blood-brain barrier, potentially leading to direct ac-tions within the Central Nervous System (CNS). S1PR modulators specifically bind to receptors located on the surface of naive and central memory lymphocytes, causing these cells to be trapped or confined within the lymph node. The investigation of the S1P pathway has resulted in the ap-proval of three S1PR modulators, namely fingolimod, siponimod, and ozanimod, as medications for the treatment of patients suffering from Multiple Sclerosis (MS). Additionally, new S1PR modulators, such as ponesimod and etrasimod, are currently being developed and tested in clini-cal trials. Research on the creation of S1P modulators in neurodegenerative illnesses is ongoing as scientists continue to explore novel possibilities for selective S1P modulators. This study provides a concise overview of sphingolipid metabolism, the mechanism by which S1P receptors are af-fected, and the structural characteristics of several small molecule S1P modulators, with a particu-lar focus on their structure-activity connections.

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开发靶向鞘磷脂-1-磷酸受体的小分子调制剂以治疗神经退行性疾病的现状

:作为一种溶血磷脂，S1P 在各种生理和病理过程中起着至关重要的作用。它通过五种不同亚型的 G 蛋白偶联受体（GPCR）（即 S1PR1 至 S1PR5）发出信号来实现这一目的。S1PR 调节剂具有穿越血脑屏障的能力，有可能直接作用于中枢神经系统（CNS）。S1PR 调节剂能与位于幼稚淋巴细胞和中枢记忆淋巴细胞表面的受体特异性结合，使这些细胞被困或限制在淋巴结内。通过对 S1P 途径的研究，芬戈莫德、西泊尼莫德和奥扎尼莫德这三种 S1PR 调节剂已被批准作为治疗多发性硬化症（MS）患者的药物。此外，目前正在开发新的 S1PR 调节剂，如蓬西莫德（ponesimod）和艾曲西莫德（etrasimod），并在临床试验中进行测试。随着科学家们不断探索选择性 S1P 调节剂的新可能性，有关在神经退行性疾病中创造 S1P 调节剂的研究也在进行之中。本研究简明扼要地概述了鞘脂代谢、S1P 受体的影响机制以及几种小分子 S1P 调节剂的结构特征，尤其关注了它们的结构与活性之间的联系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current topics in medicinal chemistry 医学-医药化学

CiteScore

6.40

自引率

2.90%

发文量

186

审稿时长

3-8 weeks

期刊介绍： Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.