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Benzisoxa thiazoles 5-LOX and mPGES-1 inhibitor and application

A technology of benzisothiazoles and isothiazoles, used in the preparation of medicines for the treatment and prevention of various inflammations, the field of benzisothiazoles

Active Publication Date: 2013-08-21
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

mPGES-1 was discovered in 1999. It is located at the end of the prostaglandin inflammatory mediator production pathway, and its expression is only up-regulated under the induction of inflammation. mPGES-1 is considered to be an inflammatory drug target that can avoid toxic side effects. mPGES-1 inhibitors enter clinical trials

Method used

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  • Benzisoxa thiazoles 5-LOX and mPGES-1 inhibitor and application
  • Benzisoxa thiazoles 5-LOX and mPGES-1 inhibitor and application
  • Benzisoxa thiazoles 5-LOX and mPGES-1 inhibitor and application

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Experimental program
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Effect test

Embodiment 2

[0045] Embodiment 2, the synthesis of bifunctional inhibitor

[0046] The synthesis method of this bifunctional inhibitor is described below by taking the compound 3-(3-methylphenyl)amino-6-nitro-1,1-dioxybenzisothiazole (PKUMDL_AAL_101) as an example.

[0047]

[0048] Reagents and conditions: (a) SOCl 2 , DMF(cat.), Dioxane, 110℃, 1.5h; (b) NEt3, THF, rt, 4~6h.

[0049] Under the protection of argon, add 0.23g (1mmol) 6-nitro-1,1,3-trioxo-2,3-dihydro-benzisothiazole and 10mL 1,4- Dioxane (Dioxane), after stirring to dissolve the solid completely, add 0.36g (3mmol) thionyl chloride (SOCl 2 ) in 0.5mL dimethylformamide (DMF) solution, heated to reflux at 110°C for 1.5h, the reaction was completed, and the solvent and excess thionyl chloride were distilled off under reduced pressure to obtain the intermediate 3-chloro-6-nitro-1, 1-Dioxo-benzisothiazole was directly carried on to the next reaction without purification. 15 mL of tetrahydrofuran, 0.3 g (3 mmol) of triethyla...

Embodiment 3

[0062] Embodiment 3, the in vitro activity of 5-LOX is measured by fluorescence spectrophotometry

[0063] The principle of fluorescence spectrophotometry is based on the reaction intermediate product 5-HPETE of 5-LOX, which can convert the fluorescent chromogenic agent H 2 DCFDA is oxidized to generate a highly fluorescent molecular DCF with an excitation wavelength of 500nm and an emission wavelength of 520nm. When measuring the activity, first add the 5-LOX enzyme to the assay buffer (50mM Tris-HCl, pH 7.5, 0.2mM ATP, 0.1mM dithiothreitol (dithiothreitol, DTT), 0.1mM EDTA, 0.5mM CaCl 2 ), incubate in a 96-well plate at 25°C for 10 min to equilibrate. Add color developer H 2 DCFDA (final concentration of 10 μM) and arachidonic acid AA substrate (final concentration of 25 μM) initiated the reaction, and the generation of fluorescent product DCF was monitored over time with a fluorescent microplate reader (excitation wavelength was 500 nm, emission wavelength was 520nm). T...

Embodiment 4

[0065] Embodiment 4, the in vitro activity of mPGES-1 measured by enzyme-linked immunosorbent assay

[0066] The enzymatic activity of mPGES-1 was characterized by quantitative measurement of PGE2 produced by mPGES-1-catalyzed conversion of the substrate PGH2. The amount of catalyzed PGE2 was determined using a PGE2 ELISA kit (Cayman). For the determination method, see the kit instructions. When measuring the activity, the substrate PGH2 was first added to a 96-well plate at a constant temperature of 4°C. Add 100 μl of enzyme to initiate the reaction. After reacting at 4°C for 1 min, 150 μl of stop solution (50 mM FeCl2 and 100 mM citric acid) was added to terminate the reaction. After the solution was diluted, the content of the product PGE2 was determined using a PGE2 enzyme-linked immunosorbent assay kit. It should be noted that the substrate PGH2 is unstable and easy to decompose at high temperature, and should be placed in a constant temperature environment at 4°C dur...

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Abstract

The invention discloses a benzisoxa thiazole compound which is used as a double-function inhibitor of 5-lipoxygenase (5-LOX) and prostaglandin E synthetase (mPGES-1), and the compound has the structure shown in the formula IV, wherein, R1, R2 and R3 represent hydrogen, alkyl, alkyloxy or halogen respectively, or R2 and R1 or R3 form a ring, thereby representing 1, 3-butadiene subunit. The external and whole blood enzyme activity test of the compound for 5-LOX and mPGES-1 confirms that the compound has the double-function inhibition activity for 5-lipoxygenase and prostaglandin E synthetase, and can be used for preparing medicaments for treating and preventing various inflammations.

Description

technical field [0001] The present invention relates to the medicine for treating and preventing various inflammations, in particular to benzisothiazole compounds as bifunctional inhibitors of 5-lipoxygenase (5-LOX) and prostaglandin E synthase (mPGES-1), and Its preparation method and the application of the compound in the preparation of medicines for treating and preventing various inflammations. Background technique [0002] Inflammation is the defense response of living tissues with vascular system to injury factors. When this defense response is overactivated or out of control, inflammatory factors will attack and damage the body's own tissues, causing diseases, which may be life-threatening in severe cases. The generation of inflammation is a complex process in which multiple molecules participate in the regulation. In the early stage of drug development, the role of the selected drug target in the overall network of the disease is considered. The development of multi-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D275/06A61K31/428A61P29/00
Inventor 来鲁华刘莹贺冲吴屹然何珊尚尔昌
Owner PEKING UNIV
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