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Glutaminyl cyclase inhibitor

A glutaminyl cyclase and inhibitor technology, applied in the field of medicinal chemistry, can solve the problems of single parent structure, poor transmembrane performance, and poor water solubility, and achieve good water solubility, high druggability, and high activity.

Active Publication Date: 2016-03-09
SHENZHEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a glutaminyl cyclase inhibitor, which aims to solve the existing QC inhibitors which have a single parent structure, poor water solubility, poor transmembrane performance, and poor activity. Limited and other issues

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: N-(3-(1H-imidazol-1-yl)propyl)-3',4'-dimethoxy-[1,1'-biphenyl]-2-amine (MQI-1 ), its synthetic route is as follows:

[0035]

[0036] a, 3',4'-dimethoxy-[1,1'-biphenyl]-2-amine: bromoaniline (5.81mmol, 1 equivalent), 3,4-dimethoxyphenylboronic acid (6.98 mmol, 1.2 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.35mmol, 0.06 equivalents) were placed in a 50ml round bottom flask , respectively add 10ml of dioxane and 10ml of 2mol / LK 2 CO 3 Solution, 100 ° C, reflux for 3h. Add saturated NaCl solution to quench the reaction, cool to room temperature, extract three times with ethyl acetate, wash once with saturated NaCl solution after combining, anhydrous NaCl 2 SO 4 After drying, the product was collected by silica gel column chromatography with a yield of 90%.

[0037] b. N-(3-bromopropyl)-3',4'-dimethoxy-[1,1'-biphenyl]-2-amine: 3',4'-dimethoxy-[1 ,1'-biphenyl]-2-amine (872.32umol, 1 equivalent)...

Embodiment 2

[0039] Example 2: 4'-fluoro-N-(3-(4-methyl-1H-imidazol-1-yl)propyl)-[1,1'-biphenyl]-2-amine (MQI-31) The synthesis of its synthetic route is as follows:

[0040]

[0041] a, 4'-fluoro-[1,1'-biphenyl]-2-amine: bromoaniline (5.81mmol, 1 equivalent), 4-fluorophenylboronic acid (6.98mmol, 1.2 equivalents) and [1,1' -Bis (diphenylphosphine) ferrocene] palladium dichloride (II) dichloromethane complex (0.35mmol, 0.06 equivalent) is placed in 50ml round bottom flask, solvent is 10ml dioxane and 10ml2mol / LK 2 CO 3 solution, at 100°C, stirred for 3 h, added saturated NaCl solution to quench the reaction, extracted three times with ethyl acetate, combined and washed once with saturated NaCl solution, anhydrous NaCl 2 SO 4 After drying, the product was collected by silica gel column chromatography with a yield of 94%.

[0042] b. N-(3-bromopropyl)-4'-fluoro[1,1'-biphenyl]-2-amine: 4'-fluoro-[1,1'-biphenyl]-2-amine (534.15 umol, 1 equivalent) and 1,3-dibromopropane (3.74mmol, 7 ...

Embodiment 3

[0044] Embodiment 3: QC inhibitor is tested to QC enzyme inhibitory activity

[0045] The schematic diagram of the QC enzyme inhibition activity test principle is as follows: figure 1 shown. The enzyme activity test was carried out in a 96-well microtiter plate, using 200ul pH8.0 Tris buffer system: 0.3mM NADH, 2.0mM freshly prepared Gln-Gln, 14mM α-ketoglutarate, 30U / ml glutamate dehydrogenase, 50mM Tris, pH8 .0 buffer solution, and finally add 0.28 μM recombinant human QC protein and the mixture of different concentrations of inhibitors, shake for 30 seconds, and use a microplate reader to dynamically detect the change in the absorption value of NADH at 340nm wavelength within 15 minutes at 25°C, every 30s Once the data is collected, according to the test results, calculate the IC of the inhibition effect of the inhibitor on the QC enzyme activity 50 Value, the test result for different QC inhibitors is shown in table 1, wherein the structural formula of QC inhibitors is: ...

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Abstract

The invention discloses a glutaminyl cyclase inhibitor. The structure of the glutaminyl cyclase inhibitor is shown in the following formula ( as shown in the description). The glutaminyl cyclase inhibitor (QC inhibitor) provided by the invention is designed according to the crystal structure of an active center of target pheron. The glutaminyl cyclase inhibitor shows favorable selectivity and specifity, and has higher druggability. The glutaminyl cyclase inhibitor is rich in parent structures, good in water solubility, good in transmembrane properties and high in activity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a glutaminyl cyclase inhibitor. Background technique [0002] Glutaminylcyclase (Glutaminylcyclase, QC, EC2.3.2.5) is an enzyme that can catalyze the intramolecular cyclization reaction of N-terminal glutamine residues such as polypeptides and proteins to generate pyroglutamic acid (pGlu). In 1963, QC was first discovered in the latex of the tropical plant papaya (Caricapapaya), and later studies confirmed that QC is distributed in plants, animals, and microorganisms. Mammalian QC is highly conserved and has no sequence homology with papaya QC, but has significant sequence homology with bacterial aminopeptidase, so animal and plant QC have different evolutionary origins. In plants, the physiological function of QC is not very clear, and it may play a certain role in the process of plant defense against pathogenic microorganisms. QC in animals has important biological function...

Claims

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Application Information

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IPC IPC(8): C07D233/61A61P25/28A61P19/02A61P29/00A61P1/16A61P35/00A61P37/02A61P19/04
CPCC07D233/61
Inventor 吴海强李满满董瑶刘志刚贺震旦邹永东郑易之余熙
Owner SHENZHEN UNIV
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