Methods and compositions for inhibition of the transitional endoplasmic reticulum atpase

A technology of compounds and substrates, which can be applied in the direction of drug combination, compound screening, active ingredients of heterocyclic compounds, etc., and can solve problems such as low toxicity

Inactive Publication Date: 2013-04-24
CALIFORNIA INST OF TECH +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Given that p97 is associated with ERAD and has a more restricted role in the UPS than the proteasome, drugs targeting p97 may retain many of the efficacy of bortezomib with less toxicity

Method used

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  • Methods and compositions for inhibition of the transitional endoplasmic reticulum atpase
  • Methods and compositions for inhibition of the transitional endoplasmic reticulum atpase
  • Methods and compositions for inhibition of the transitional endoplasmic reticulum atpase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0227] Embodiment 1, commercially available compound

[0228] Compounds shown in Tables 1-33 (as indicated in the table) were either synthesized or commercially available, where S indicates synthetic and P indicates commercially available. Table 34 below provides company information for commercially available compounds.

[0229] Table 34

[0230] compound#

[0231] I-27

Embodiment 2

[0232] Embodiment 2, compound synthesis

[0233] In general, the compounds of the invention (including salts and solvates thereof) can be prepared using known techniques of organic synthesis and can be synthesized according to any of a number of possible synthetic routes. Since the reactions to prepare the compounds of the present invention can be carried out in suitable solvents, the suitable solvents can be easily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), intermediates or products at the temperatures at which the reactions are carried out, i.e. temperatures that can vary from the freezing point of the solvent to the boiling point of the solvent . A given reaction can be carried out in one solvent or in a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected.

[0234] The prepar...

Embodiment 3

[0258] Embodiment 3, the synthesis of compound derivative LII, LIII, LIV, LV and LVI

[0259] Refer to the synthetic scheme of Kohn et al., 1983, J. Am. Chem. Soc, 105, 4106-4108.

[0260]

[0261]

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PUM

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Abstract

Compounds of Formulas I-XLIII are identified as direct inhibitors of p97 ATPase or of the degradation of a p97-dependent ubiquitin-proteasome system (UPS) substrate. Methods and compositions are disclosed for inhibiting p97 ATPase and the degradation of a p97-dependent UPS substrate, and for identifying inhibitors thereof.

Description

[0001] Cross-references to related applications: [0002] This application claims priority to and claims the rights of US Provisional Application No. 61 / 332,667, filed May 7, 2010, the entire contents of which are incorporated herein by reference. [0003] Statement Regarding Federal Sponsorship of Research or Development: [0004] This invention was made with government support No. MH085687 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0005] Embodiments of the invention relate to selective inhibitors of the ubiquitin-proteasome system (UPS). In particular, the present invention identifies inhibitors of transitional endoplasmic reticulum (p97) ATPases and ubiquitin substrates. Background technique [0006] The ubiquitin-proteasome system (UPS) comprises one of the most important mechanisms for the post-translational regulation of protein function in eukaryotic cells. The UPS contains hundreds of enzy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/517A61K31/53A61K31/4184A61P35/00
CPCG01N2500/02A61K31/517A61K31/53C12Q1/485A61K31/538C12Q1/42A61K31/4184A61P35/00A61P35/02A61P43/00
Inventor R·J·德赛T-F·周K·李F·J·舍嫩K·J·弗兰科夫斯基J·奥贝S·W·格里茨H-J·周
Owner CALIFORNIA INST OF TECH
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