LH2-051(LH2-051) - 药物靶点：CDK9 x DAT x TFEB_在研适应症：阿尔茨海默症_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

作用机制

CDK9 modulators(Cyclin-dependent kinase 9 modulators)、DAT调节剂(多巴胺转运体调节剂)、TFEB modulators(transcription factor EB modulators)

治疗领域

神经系统疾病

在研适应症

阿尔茨海默症

非在研适应症-

原研机构

南京中医药大学

在研机构

南京中医药大学

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)临床前

特殊审评-

结构

分子式C27H34N2O3

InChIKeyWBEFXEHFEBYZEJ-UHFFFAOYSA-N

CAS号2358754-22-8

关联

100 项与 LH2-051 相关的临床结果

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100 项与 LH2-051 相关的转化医学

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100 项与 LH2-051 相关的专利（医药）

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1

项与 LH2-051 相关的文献（医药）

2024-06-13·Journal of Medicinal Chemistry

Discovery and Optimization of Tetrahydroisoquinoline Derivatives To Enhance Lysosome Biogenesis as Preclinical Candidates for the Treatment of Alzheimer’s Disease

Article

作者: Shou, Haowen ; Gu, Zhiyong ; Hu, Yuting ; Wang, Jing ; Wang, Ning ; Zhou, Jianhui ; Liu, Hong ; Zhang, Zhenwei ; Zhou, Yu ; Li, Yang ; Cheng, Xi ; Wang, Mengxue

More than 55 million individuals are suffering from Alzheimer's disease (AD), while the effective therapeutic strategies remain elusive. Our previous study identified a lysosome-enhancing lead compound LH2-051 with a tetrahydroisoquinoline scaffold through a novel dopamine transporter-cyclin-dependent kinase 9-transcription factor EB (DAT-CDK9-TFEB) regulation mechanism to promote TFEB activation and lysosome biogenesis. Here, we launched a comprehensive structure-activity relationship study for LH2-051, and 47 new derivatives were designed and synthesized, in which several compounds exhibited remarkable lysosome-enhancing activities. Notably, compounds 37 and 45 exhibited more favorable TFEB activation and lysosome biogenesis capabilities, good safety profiles, and excellent pharmacokinetic profiles with high brain penetration. Further investigations demonstrated that both compounds significantly enhance the clearance of Aβ aggregates and ameliorate the impairment of learning, memory, and cognition in APP/PS1 mice. Overall, these results indicated that compounds 37 and 45 are promising preclinical drug candidates for the treatment of AD.

100 项与 LH2-051 相关的药物交易

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