Application of 5-nitro-1H-indazol-3-carbonitrile to medicament preparation
A nitro, indazole technology, applied in the application field of derivatives in the preparation of medicines, can solve the problem of not finding the relevant reports on the application of DL0805 for preventing and treating vascular diseases, and achieves the effect of good application and development prospects.
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Embodiment 1
[0032] Example 1: Evaluation of the inhibitory effect of DL0805 on Rho kinase activity.
[0033] In this embodiment, 6 positive control wells and 6 negative control wells are set on each plate in a white opaque 96-well plate. Add 5 μL compound, 10 μL 0.25 μM Rho kinase, 10 μL 1 μM Rho kinase specific substrate S6peptide and 25 μL 1 μM ATP. After mixing evenly, react at 37°C for 1 hour, add the chromogenic reagent Kinase-Glo, incubate at room temperature for 10min, and read. And calculate the inhibition rate (%) of sample to Rho kinase according to the following formula: where M com represents the average value of the compound; M neg represents the mean value of the negative control; M pos Represents the mean of positive controls. Dilute 10 concentrations of DL0805 in two-fold ratio, and finally calculate the IC of DL0805 for Rho kinase according to the measurement results 50 value. The results show that DL0805 can inhibit the activity of Rho kinase in a dose-dependent ...
Embodiment 2
[0034] Example 2: Effect of DL0805 on norepinephrine pre-stimulated vascular ring contraction.
[0035]As experimental animals, 6 male SD rats, weighing 250-300 g, were selected. After the rats were killed by decapitation, the thoracic aorta was quickly taken out, cut into 2-3mm long vascular rings, and placed in 10 mL of K-H solution (37°C constant temperature, and continuously fed with 95% oxygen and 5% carbon dioxide). In the bath of mixed gas), the tension change is transmitted and recorded in the BL-420S biological function experiment system. The vascular ring was stabilized at 1.2g tension for 60 minutes, and the K-H solution was changed every 20 minutes during this period. Stimulate the vascular ring with 60mM KCl to shrink the vascular ring. After reaching the maximum amplitude, flush the vascular ring twice to restore the vascular ring to the state before the stimulation, a total of 2 times. Add 1 μM norepinephrine, give 10 μM acetylcholine after reaching the maximu...
Embodiment 3
[0037] Example 3: Effect of DL0805 on KCl pre-stimulated vascular ring contraction.
[0038] The preparation method of the blood vessel ring for tension measurement is the same as that in Example 3.
[0039] High potassium can cause blood vessels to constrict. In this example, 60 mM KCl was added to the reaction system to make the blood vessels contract. DL0805 with a cumulative concentration of 1, 2, 5, 10, 25, and 50 μM had a significant effect on the shrinkage of both non-endothelial and endothelial vascular rings caused by KCl. Inhibitory effect, the inhibitory effect was enhanced with the increase of the concentration, and showed a dose-effect relationship. To determine the relaxation effect of DL0805 on the vasoconstriction induced by norepinephrine and the pharmacological effect and application of prevention and treatment of vascular diseases induced by abnormal increase of vascular tension.
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