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Application of benzamide derivatives in the preparation of caspase-1 inhibitors

A technology of derivatives and benzamides, applied in the field of medicine, can solve problems such as difficult clinical treatment, loss of drug efficacy, and poor druggability of polypeptide drugs, and achieve the effects of prolonging latent time, inhibiting seizures, and treating febrile convulsions

Active Publication Date: 2018-12-04
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, Caspase-1 inhibitors such as Ac-YVAD-cmk are mostly polypeptide drugs, which are easily limited by pharmacokinetics. For example, polypeptide drugs will be degraded into small molecular amino acids in the gastrointestinal tract after being taken orally. absorption, leading to loss of efficacy
Therefore, peptide drugs have poor druggability and are difficult to be used in clinical treatment

Method used

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  • Application of benzamide derivatives in the preparation of caspase-1 inhibitors
  • Application of benzamide derivatives in the preparation of caspase-1 inhibitors
  • Application of benzamide derivatives in the preparation of caspase-1 inhibitors

Examples

Experimental program
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Effect test

Embodiment 1

[0055] The preparation of embodiment one benzamide derivatives and its biological activity assay

[0056] 1. Use molecular docking methods (including glide HTVS, SP and XP) to design compounds, use the crystal structure of Caspase-1 (PDB code: 3NS7) as the starting structure for molecular docking, screen active compounds and analyze the binding mechanism. see figure 1 ,A1-A7 is 3-(3-(thiophene-2-carboxamide)benzamido)methyl benzoate; 5-((3-((2,4-dimethoxyphenyl)carbamoyl )phenyl)amino)-5-oxopentanoic acid methyl ester; (S)-1-(2-chlorobenzamide)-5-oxopyrrolidine-3-carboxylic acid ethyl ester; 4-(4 -(2-Chlorobenzoyl)phenylsulfonamide)methyl benzoate; (R)-4-oxo-4-((2-((1-phenylethyl)carbamoyl)phenyl) Amino)butyl; 4-((4-((5-Chloro-2-methoxyphenyl)carbamoyl)phenyl)amino)-4-oxobutanoic acid; (Z)-(2-Benzene Binding conformation of amido-3-(benzo[d][1,3]dioxol-5-yl)acryloyl)-D-glutamic acid in the active pocket of Caspase-1 (compounds using stick The shape model shows); B1-B7 is t...

Embodiment 2

[0061] The antidepressant effect of embodiment dibenzamide derivatives in mouse febrile convulsion model

[0062] 1. Animal model of febrile convulsion: C57BL / 6J mice and Casp1 - / - Mice, both male and female, were weighed, and rectal temperature (basal body temperature) was recorded. Place the pups in an oven with a temperature of 41°C, and record the rectal temperature every 5 minutes until the pups have convulsions induced by high temperature. , turning in circles; 5, standing unsteadily, falling, tonic-clonic of limbs. Once the animal falls and limb clonus behavior, it is considered as the first seizure (1st seizure), the time from being placed in the oven to the seizure is recorded as the latent time, and the rectal temperature at this time is measured as the seizure threshold temperature . Once the animal had convulsions, it was moved to a flat plate at room temperature to rest for 2 minutes, and then put the animals back into the oven until the convulsions reappeared,...

Embodiment 3

[0074] Embodiment three toxic and side effects are measured

[0075] 1. Measurement of respiratory rate and open field experiment: P8 C57BL / 6J mice were injected with solvent (2‰DMSO saline) and 3-(3-(thiophene-2-carboxamide)benzamido)benzene into tail vein Methyl formate (0.75 mg / kg), after which the respiratory rate per minute was recorded, see Figure 17 . Carry out the open field experiment after 5 minutes, through the animal behavior analysis system of the open field experiment, measure the distance that the experiment moves in 15 minutes (exercise ability) and the time ratio of immobility (sedation effect), refer to Figure 18 , 19. 6 in each group above.

[0076]2. In vivo EEG (Electroencephalogram, EEG) recording and analysis of young mice: C57BL / 6J mice at P8 were anesthetized with isoflurane gas (4% induction, 2% maintenance) and then fixed in a small animal stereotaxic instrument. Lateral hippocampus (AP:-1.3mm, L:-1.5mm, V:-1.6mm) and prefrontal cortex (AP:-0.5...

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Abstract

The invention provides application of a benzamide derivative and pharmaceutical salt thereof in preparing a Caspase-1 selective inhibitor and anti-convulsion medicine. The novel Caspase-1 selective inhibitor 3-(3-(thiophene-2-formamide)benzamido)methyl benzoate is obtained through screening, it is provided through molecule, cell and whole animal level experiments that 3-(3-(thiophene-2-formamide)benzamido)methyl benzoate can effectively inhibit Caspase-1 enzyme activity, inhibit the attack of febrile convulsions of whole animals, prolong the latent time of the attack of febrile convulsions, increase the threshold value of the attack of febrile convulsions and decrease the proportion of the attack of febrile convulsions, and has no obvious acute or chronic toxic or side effect, and an experimental basis is provided for application of 3-(3-(thiophene-2-formamide)benzamido)methyl benzoate in treating febrile convulsions.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to benzamide derivatives and their medical applications, in particular to the application of benzamide derivatives in the preparation of Caspase-1 inhibitors and anti-convulsant drugs. Background technique [0002] Febrile seizures (Febrile seizures, FS) are convulsions caused by high fever, which is the most common type of convulsions in infants and young children. The incidence rate in the south is as high as 16%. Febrile convulsions are caused by sudden abnormal excessive electrical discharge. Excluding factors such as intracranial infection or metabolic disorder, there is currently a lack of effective treatment strategies. At present, the clinical treatment of febrile convulsions in children mainly uses steroidal anti-inflammatory drugs as auxiliary antiepileptic drugs. Although commonly used antipyretic and analgesic drugs such as paracetamol and ibuprofen can effectively relieve fever ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/381A61K31/196A61K31/4015A61K31/63A61K31/36A61P25/08
CPCA61K31/196A61K31/36A61K31/381A61K31/4015A61K31/63
Inventor 陈忠唐杨顺冯博侯廷军孙慧涌胡薇薇
Owner ZHEJIANG UNIV
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