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Application of carboxamide triazole compound or salt thereof as sphingosine kinase 2 inhibitor

A kind of carboxamine triazoles, sphingosine kinase technology, applied in the field of medicine

Active Publication Date: 2021-06-11
GUANGDONG YINZHU PHARMACEUTICAL TECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, so far, there is no report on the regulation of sphingomyelin signaling by carboxyaminotriazoles

Method used

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  • Application of carboxamide triazole compound or salt thereof as sphingosine kinase 2 inhibitor
  • Application of carboxamide triazole compound or salt thereof as sphingosine kinase 2 inhibitor
  • Application of carboxamide triazole compound or salt thereof as sphingosine kinase 2 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] This embodiment is used to illustrate the half-inhibitory concentration (IC) of CAI and CTO for the inhibitory effect of SPHK2 enzyme activity 50 )

[0078] The inhibition of SPHK2 enzyme activity was detected by Off-chip Mobility Shift Assay:

[0079] ①. The compounds to be tested (CAI, CTO and ABC294640) were dissolved in dimethyl sulfoxide (DMSO) to prepare a solution whose concentration was 100 times the final concentration of the test. The solution was then diluted 25 times with assay buffer (20 mM HEPES, 0.01% Triton X-100, 1 mM DTT, pH 7.5) to obtain a 4-fold concentration compound solution (4×compound solution). In a similar manner, a 4x positive control solution was prepared using the positive control (PF-543).

[0080] ②. Use reagent buffer (20mM HEPES, 0.01% Triton X-100, 5mM DTT, pH 7.5) to configure 4× substrate / ATP / metal solution (see Table 1 for the concentration of substrate, ATP and metal), and use assay buffer Make up 2× kinase solution.

[0081] C...

Embodiment 2

[0094] This example is used to illustrate that CAI and CTO can selectively inhibit the enzymatic activity of SPHK2.

[0095] SPHK includes two subtypes, SPHK1 and SPHK2. In order to clarify the selectivity of CAI and CTO for the inhibition of SPHK2 enzyme activity, the inhibition rate (%) of CAI and CTO on SPHK1 and SPHK2 enzyme activity at the concentration of 40 μM was detected respectively. The method for detecting the enzyme inhibitory activity of SPHK2 is the same as that in Example 1. When detecting the enzyme activity inhibition rate (%) to SPHK1, replace SPHK2 kinase with SPHK1 kinase, the concentration of each component in the substrate / ATP / metal solution is shown in Table 3, and other operations are with the enzyme inhibition of SPHK2 among the embodiment 1 Activity detection method.

[0096] Concentration of each component in the substrate / ATP / metal solution in table 3

[0097]

[0098] The results showed that 40 μM CAI inhibited the enzyme activities of SPHK1...

Embodiment 3

[0100] This example is used to illustrate that CAI's inhibitory effect on SPHK2 enzyme activity is not achieved by affecting its expression.

[0101] In order to clarify whether the inhibitory effect of CAI on SPHK2 enzyme activity is achieved by affecting its expression, rat collagen-induced arthritis (collagen-induced arthritis, CIA) was established, and the protein expression levels of SPHK1 and SPHK2 in rat joint synovium were detected:

[0102] ①. Preparation of rat CIA model: Dissolve bovine type II collagen (CII) in 50 mM acetic acid, stir at 4°C to fully dissolve it, the concentration is 4 mg / mL, put it in a refrigerator at 4°C overnight, and mix with Mix equal volumes of complete Freund's adjuvant containing 4 mg / mL inactivated BCG, fully emulsify in ice bath, and make CⅡ emulsion. On the 0th day (d0), except the control group, other groups were intradermally injected with 0.2 mL emulsion at the base of the tail and back of each rat. On d7, except for the control gro...

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Abstract

The invention belongs to the field of medicines, and particularly relates to application of a carboxamide triazole compound or a salt thereof as a sphingosine kinase 2 (SPHK2) inhibitor. The carboxamide triazole compound or the pharmaceutically acceptable salt thereof has an efficient selective SPHK2 inhibition effect, and can be used as a prophylactic and / or therapeutic agent for SPHK2 related diseases, especially renal fibrosis.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the application of carboxyaminotriazole compounds or salts thereof as sphingosine kinase 2 (SPHK2) inhibitors. The present invention also relates to the use of carboxyaminotriazole compounds or pharmaceutically acceptable salts thereof as preventive and / or therapeutic agents for SPHK2-related diseases. In particular, the present invention relates to the use of carboxyaminotriazole compounds or pharmaceutically acceptable salts thereof as preventive and / or therapeutic agents for renal fibrosis. Background technique [0002] Sphingomyelin is the main component of cell membrane, and its metabolites such as ceramide (Cer), sphingosine (Sph) and sphingosine-1-phosphate (S1P) are biologically active. Important signaling molecules involved in the regulation of cell growth, differentiation, aging and death and other signal transduction processes. Among them, Cer and Sph promote cell...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4192A61P13/12
CPCA61K31/4192A61P13/12
Inventor 叶菜英李宗森朱蕾池研生
Owner GUANGDONG YINZHU PHARMACEUTICAL TECHNOLOGY CO LTD
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