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Methods and agents for inhibiting dynamin-dependent endocytosis

A dynamin and cell-inhibiting technology, applied in drug combinations, nitrile/isonitrile active ingredients, organic chemistry, etc., can solve problems such as weak specificity and limited effect

Inactive Publication Date: 2007-03-28
UNIV OF NEWCASTLE RES ASSOCS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Each has weak specificity and limited effect

Method used

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  • Methods and agents for inhibiting dynamin-dependent endocytosis
  • Methods and agents for inhibiting dynamin-dependent endocytosis
  • Methods and agents for inhibiting dynamin-dependent endocytosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Example 1: Identification of Inhibition of Tyrosine Phosphorylation Inhibitors of Dynamin GTPase Activity

[0160] 1.1 Materials and methods

[0161] Phosphatidylserine, 1,2-glycerol dioleate, calmodulin, ATP, GTP, leupeptidase, phenylmethylsulfonyl fluoride, Tween 80, bis(sulfosuccinimidyl)octyl Basinate (BS3) and glutathione sepharose were obtained from Sigma. Papain and antipain dihydrochloride were obtained from Boehringer Mannheim (Federal Republic of Germany). Gel electrophoresis reagents and apparatus were from Bio-Rad. (3000 Ci / mmol) and (25 μCi / mmol) was obtained from Amersham plc, UK. Protein molecular weight markers and chromatography resins were from Pharmacia. All other reagents were of analytical grade or better.

[0162] 1.1.1 Protein preparation

[0163] The plasmid of GST-Amph2-SH3 (Muscle Amph2) (Butler et al., 1997) was provided by Pieto DeCamilli, Yale, Conneticut, USA, placed in pGEX2T vector. The plasmid was grown in E. coli and the GST-A...

Embodiment 2

[0200] Example 2: Development of Tyrosine Phosphorylation Inhibitor Analogs

[0201]

[0202] Di-Tyrosine Phosphorylation Inhibitor (1) and Tyrosine Phosphorylation Inhibitor A47 (2)

[0203] 2.1 Development of analogues

[0204] The structures of bis-tyrosine phosphorylation inhibitor and tyrosine phosphorylation inhibitor A47 are shown above. The structural similarity of these 3,4-dihydroxybenzene compounds and the presence of cyanamide or thioamide structures suggest that these groups are important for dynamin inhibition. These features can solve the problem of library development and synthesis, and there are two libraries for determining the type and number of aromatic substituents that determine activity, the need for symmetrical synthesis (1vs2), and the location of bis-tyrosine phosphorylation inhibitors. The importance of the length of the central alkane spacer between the two amino moieties These libraries are referred to as library 1 (dimeric compounds) and li...

Embodiment 3

[0315] Example 3: Development of Prodrugs

[0316] Prodrugs of bis-tyrosine phosphorylation inhibitors and their analogs were developed to increase the permeability of cell membranes and thus increase the potency of drugs in cells. A suitable reaction to provide a prodrug of a dimerized tyrosine phosphorylation inhibitor compound is illustrated in Scheme 5. Bis-tyrosine phosphorylation inhibitors are examples of initiating agents. The dimer tyrosine phosphorylation inhibitor compound is stirred together with the appropriate anhydride or acid chloride (in molar excess) in pyridine / N,N-dimethylformamide (DMF) solution in the presence of an appropriate catalyst such as dimethyl Aminopyridine (DMAP). In some cases, the solution required reflux to complete the reaction. After the reaction is complete, the esterified product is purified by recrystallization or chromatography. Examples of prodrugs developed are shown in Tables 2 and 3.

[0317]

[0318] Scheme 5. Synthesis of...

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Abstract

There are disclosed methods for inhibiting dynamin-dependent endocytosis in cells comprising treating the cells with an effective amount of a compound of formula (I), or a dimeric tyrphostin, physiologically acceptable salt, or prodrug thereof. Compounds useful in the methods described are also provided. The inhibition of dynamin-dependent endocytosis of cells is applicable to the treatment of epilepsy and neurological disorders and conditions.

Description

field of invention [0001] The present invention relates to agents for inhibiting dynamin-dependent cellular internalization, and methods of preventing or treating diseases or disorders mediated by dynamin-dependent cellular internalization. Background of the invention [0002] Mammalian cells take up nutrients from the outside and recycle the cell membrane through endocytosis, which involves the formation of numerous vesicles within the plasma membrane. Small vesicles range in size from large phagosomes, followed by clathrin-coated vesicles, to tiny synaptic vesicles (SVs). The mechanism of endocytosis contributes to many cellular functions, including uptake of extracellular nutrients, regulation of cell surface receptor expression and signaling, antigen expression, and maintenance of synaptic transmission. [0003] The endocytosis pathway has two notable biochemical features. The first is rapid synaptic vesicle internalization (SVE), which follows vesicle efflux at the ne...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/275C07C255/34C07C255/40C07D407/12A61P25/00
Inventor A·麦克拉斯基P·J·鲁宾逊T·A·希尔
Owner UNIV OF NEWCASTLE RES ASSOCS
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