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Applications of 2,4-disubstituted thiazoles derivatives being taken as DHODH (dihydroorotate dehydrogenase) inhibitor

A disubstituted, thiazole-based technology, used in the application field of 2,4-disubstituted thiazole derivatives as DHODH inhibitors

Inactive Publication Date: 2013-04-03
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the present invention, the inhibitory effect of novel 2,4-disubstituted thiazole compounds on human DHODH is reported for the first time, and the compounds of the present invention are used in the preparation of medicines for diseases mediated by DHODH (such as inflammatory response, autoimmune disease, tumor, etc.) Use has never been reported

Method used

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  • Applications of 2,4-disubstituted thiazoles derivatives being taken as DHODH (dihydroorotate dehydrogenase) inhibitor
  • Applications of 2,4-disubstituted thiazoles derivatives being taken as DHODH (dihydroorotate dehydrogenase) inhibitor
  • Applications of 2,4-disubstituted thiazoles derivatives being taken as DHODH (dihydroorotate dehydrogenase) inhibitor

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Experimental program
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Effect test

Embodiment 1

[0070] Example 1: The compounds provided by the present invention were obtained through virtual screening by computer-aided drug design method.

specific example 1 to 21

[0072] Using the complex crystal structure of DHODH and its small molecule inhibitor Brequinar analogue (PDB database number 1D3G) as the receptor, the 230,000 compound structures in the SPECS compound database were docked into the receptor using the Glide docking software, and the docking mode was successively adopted Glide's "standard precision mode" (SP mode) and "extreme precision mode" (XP mode), and then according to the GlideGscore to score and sort the docking mode of each compound, carefully observe and analyze the docking binding mode of each compound and DHODH and finally Select 21 compound structures to carry out the in vitro test experiment of inhibiting DHODH activity, and all compounds are purchased from Holland SPECS company ( www.specs.net ).

Embodiment 2

[0073] Embodiment 2: The compound provided by the invention is to the in vitro inhibitory effect of dihydroorotate dehydrogenase (DHODH) activity

[0074] Materials: The plasmid containing the full-length human DHODH gene was donated by Prof.Jon Clardy (Harvard Medical School) (J.Bio.Chem.2008, 283(50), 35078-35085) or can be obtained from Aurui Dongyuan Biotechnology Co., Ltd. purchased. The pET-19b vector, E.coli DH5α and E.coli BL21(DE3) strains were purchased from Novagen. Restriction enzymes Nde I and Bam HI were purchased from NEB Company. Primers were synthesized by Shanghai Yingjun Biotechnology Co., Ltd. Other reagents were purchased from sigma. 〔The materials owned by individuals or organizations are not available to the public. Therefore, the above-mentioned plasmids may lead to insufficient disclosure of the instructions, and ultimately lead to the failure of the application to be authorized. Suggestions: (1) Provide the source of the literature, and at the same...

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Abstract

The invention relates to applications of a 2,4-disubstituted thiazoles compound in pharmaceutical chemistry and pharmacotherapy. Specifically, the invention relates to applications of a compound shown in formula I (described in the specification) and a medicinal composition of the compound in preparation of medicines used for treating diseases related to DHODH (dihydroorotate dehydrogenase).

Description

technical field [0001] The invention relates to the application of 2,4-disubstituted thiazole compounds in the fields of medicinal chemistry and pharmacotherapy. Specifically, the application of 2,4-disubstituted thiazole compounds as dihydroorotate dehydrogenase (DHODH) inhibitors in the treatment of DHODH-mediated diseases (such as tumors, inflammatory reactions). Background technique [0002] Dihydroorotate dehydrogenase (Dihydroorotate dehydrogenase, DHODH) is an enzyme that catalyzes the dehydrogenation of dihydroorotate to convert it into orotate. This process belongs to the fourth step reaction of pyrimidine de novo synthesis pathway, so DHODH is the key enzyme of nucleic acid pyrimidine synthesis. Inhibition of DHODH can block the synthesis of nascent pyrimidines, resulting in obstacles to DNA and RNA synthesis. For most organisms, pyrimidine bases can be obtained through de novo synthesis and salvage pathways, but rapidly differentiating human cells, such as activ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61K31/427A61K31/426A61P35/00A61P29/00A61P37/02
Inventor 李洪林刁妍妍黄瑾赵振江崔坤强卢伟强许鸣豪韩乐徐玉芳
Owner EAST CHINA UNIV OF SCI & TECH
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