更新于：2024-11-21

Ethaverine Hydrochloride

盐酸依沙维林

更新于：2024-11-21

概要

概要

基本信息

药物类型

小分子化药

别名

Ethapin、Ethaquin

靶点

5-HT2 receptor x D2 receptor

作用机制

5-HT2 receptor拮抗剂(5-羟色胺2受体拮抗剂)、D2 receptor拮抗剂(多巴胺D2受体拮抗剂)

治疗领域

神经系统疾病皮肤和肌肉骨骼疾病

在研适应症

肌肉痉挛

非在研适应症-

原研机构-

在研机构-

非在研机构-

最高研发阶段批准上市

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C24H29NO4

InChIKeyZOWYFYXTIWQBEP-UHFFFAOYSA-N

CAS号486-47-5

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关联

100 项与盐酸依沙维林相关的临床结果

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100 项与盐酸依沙维林相关的转化医学

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100 项与盐酸依沙维林相关的专利（医药）

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项与盐酸依沙维林相关的文献（医药）

2024-05-10·ACS Pharmacology & Translational Science

Ethaverine and Papaverine Target Cyclin-Dependent Kinase 5 and Inhibit Lung Cancer Cell Proliferation and Migration

Article

作者: Baratte, Blandine ; Laure, Arthur ; Morris, May C ; Bach, Stéphane ; Bihel, Frederic ; Royet, Chloé ; Peyressatre, Marion

CDK5 kinase plays a central role in the regulation of neuronal functions, and its hyperactivation has been associated with neurodegenerative pathologies and more recently with several human cancers, in particular lung cancer. However, ATP-competitive inhibitors targeting CDK5 are poorly selective and suffer limitations, calling for new classes of inhibitors. In a screen for allosteric modulators of CDK5, we identified ethaverine and closely related derivative papaverine and showed that they inhibit cell proliferation and migration of non small cell lung cancer cell lines. Moreover the efficacy of these compounds is significantly enhanced when combined with the ATP-competitive inhibitor roscovitine, suggesting an additive dual mechanism of inhibition targeting CDK5. These compounds do not affect CDK5 stability, but thermodenaturation studies performed with A549 cell extracts infer that they interact with CDK5 in cellulo. Furthermore, the inhibitory potentials of ethaverine and papaverine are reduced in A549 cells treated with siRNA directed against CDK5. Taken together, our results provide unexpected and novel evidence that ethaverine and papaverine constitute promising leads that can be repurposed for targeting CDK5 in lung cancer.

2023-12-01·European Journal of Medicinal Chemistry

Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors

Article

作者: Li, Zhewen ; Zou, Yi ; Liu, Jiayuan ; Su, Haixia ; Shao, Qiang ; Zhang, Xianglei ; Li, Minjun ; Chen, Guofeng ; Xu, Yechun

Phosphodiesterase-4 (PDE4) and PDE5 responsible for the hydrolysis of intracellular cAMP and cGMP, respectively, are promising targets for therapeutic intervention in a wide variety of diseases. Here, we report the discovery of novel, drug-like PDE4 inhibitors by performing a high-throughput drug repurposing screening of 2560 approved drugs and drug candidates in clinical trial studies. It allowed us to identify eight potent PDE4 inhibitors with IC₅₀ values ranging from 0.41 to 2.46 μM. Crystal structures of PDE4 in complex with four compounds, namely ethaverine hydrochloride (EH), benzbromarone (BBR), CX-4945, and CVT-313, were further solved to elucidate molecular mechanisms of action of these new inhibitors, providing a solid foundation for optimizing the inhibitors to improve their potency as well as selectivity. Unexpectedly, selectivity profiling of other PDE subfamilies followed by crystal structure determination revealed that CVT-313 was also a potent PDE5 inhibitor with a binding mode similar to that of tadalafil, a marketed PDE5 inhibitor, but distinctively different from the binding mode of CVT-313 with PDE4. Structure-guided modification of CVT-313 led to the discovery of a new inhibitor, compound 2, with significantly improved inhibitory activity as well as selectivity towards PDE5 over PDE4. Together, these results highlight the utility of the drug repurposing in combination with structure-based drug design in identifying novel inhibitors of PDE4 and PDE5, which provides a prime example for efficient discovery of drug-like hits towards a given target protein.

2022-09-01·Research in Pharmaceutical Sciences

Discovery of novel inhibitors of ghrelin O-acyltransferase enzyme

Article

作者: Amanlou, Massoud ; Hosseini, Faezeh Sadat ; Ghassempour, Alireza

Background and purpose:Ghrelin is known as a hunger hormone and plays a pivotal role in appetite, food intake, energy balance, glucose metabolism, and insulin secretion, making it a potential target for the treatment of obesity and type 2 diabetes. The essential maturation step of ghrelin to activate the GHS-R1a is the octanoylation of the Ser3, which is catalyzed by the ghrelin O-acyltransferase enzyme (GOAT) enzyme. Therefore, the inhibition of GOAT may be useful for treating ghrelin-related diseases.Experimental approach:To discover the novel inhibitors against GOAT enzyme by a fast and accurate computational method, here, we tried to develop the homology model of GOAT. Subsequently, the generated model was stabilized by molecular dynamics simulation. The consecutive process of docking, pharmacophore mapping, and large-scale virtual screening were performed to find the potential hit compounds.Findings / Results:The homology model of the GOAT enzyme was generated and the quality of 3D structures was increased to the highest level of > 99.8% of residue in allowed regions. The model was inserted into the lipid bilayer and was stabilized by molecular dynamics simulation in 200 ns. The sequential process of pharmacophore-based virtual screening led to the introduction of three compounds including ethaverine, kaempferitrin, and reglitazar as optimal candidates for GOAT inhibition.Conclusion and implications:The results of this study may provide a starting point for further investigation for drug design in the case of GOAT inhibitors and help pave the way for clinical targeting of obesity and type 2 diabetes.

100 项与盐酸依沙维林相关的药物交易

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