LEI-515(LEI-515) - 药物靶点：MAGL_在研适应症：炎症，疼痛_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

MAGL

作用机制

MAGL抑制剂(单甘油酯脂肪酶抑制剂)

治疗领域

神经系统疾病其他疾病

在研适应症

炎症疼痛

非在研适应症-

原研机构

在研机构

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C24H26Cl2F2N2O3S

InChIKeyWYHRZGBTLDYJGW-PCRMYRMASA-N

CAS号2702249-95-2

关联

100 项与 LEI-515 相关的临床结果

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100 项与 LEI-515 相关的转化医学

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100 项与 LEI-515 相关的专利（医药）

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1

项与 LEI-515 相关的文献（医药）

2024-07-25·Journal of Medicinal Chemistry

Structure–Activity Relationship Studies of Aryl Sulfoxides as Reversible Monoacylglycerol Lipase Inhibitors

Article

作者: Deng, Hui ; Huizenga, Mirjam C. W. ; Bakker, Renze ; van der Wel, Tom ; van den Berg, Richard J. B. H. N. ; Mohr, Florian ; Amedi, Avand ; van der Stelt, Mario ; van Boeckel, Constant A.A. ; Jiang, Ming

Monoacylglycerol lipase (MAGL) is the key enzyme for the hydrolysis of endocannabinoid 2-arachidonoylglycerol (2-AG). The central role of MAGL in the metabolism of 2-AG makes it an attractive therapeutic target for a variety of disorders, including inflammation-induced tissue injury, pain, multiple sclerosis, and cancer. Previously, we reported LEI-515, an aryl sulfoxide, as a peripherally restricted, covalent reversible MAGL inhibitor that reduced neuropathic pain and inflammation in preclinical models. Here, we describe the structure-activity relationship (SAR) of aryl sulfoxides as MAGL inhibitors that led to the identification of LEI-515. Optimization of the potency of high-throughput screening (HTS) hit 1 yielded compound ±43. However, ±43 was not metabolically stable due to its ester moiety. Replacing the ester group with α-CF₂ ketone led to the identification of compound ±73 (LEI-515) as a metabolically stable MAGL inhibitor with subnanomolar potency. LEI-515 is a promising compound to harness the therapeutic potential of MAGL inhibition.

100 项与 LEI-515 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
炎症	临床前	美国	Indiana University	2023-12-05
炎症	临床前	荷兰	University of Leiden	2023-12-05
疼痛	临床前	美国	Indiana University	2023-12-05
疼痛	临床前	荷兰	University of Leiden	2023-12-05