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Sulfonamide compound and application thereof in preparation of medicine for treating autoimmune diseases
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An autoimmune and compound technology, applied in the field of medicine, can solve problems such as glucose intolerance, and achieve the effect of potential application value
Pending Publication Date: 2022-07-05
ZHEJIANG UNIV
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But long-term use of glucocorticoids is limited by severe side effects, manifested in hypertension and major metabolic side effects, such as glucose intolerance, muscleatrophy, skinthinning, and osteoporosis
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[0075] Experimental principle: Use structure-based virtual screening to predict the binding mode and binding free energy between compounds in the compound database and glucocorticoid receptors, and screen small molecule compounds that can bind to glucocorticoid receptors.
[0076] Experimental method: Based on the crystal structure of the glucocorticoid receptor (PDB number: 6EL9), the Glide molecular docking module of the Schrodinger molecular simulationsoftwarepackage was used to conduct a structure-based virtual screening of the chemdiv small molecule database, and the best 3000 compounds were scored. Conformational analysis was performed and 88 compounds were finally purchased for activity screening.
[0077] Experimental results: 24 potential glucocorticoid analogs were screened and had different chemical backbones ( figure 1 ).
[0078] 2. Evaluation experiment of anti-inflammatory ability of glucocorticoid receptor
[0...
Embodiment 2
[0118] Taking HP-19 as the lead compound, the analogs were obtained in two ways: 1) The analogs containing N-phenylbenzenesulfonamide were selected in the Chemdiv compound library, and the binding mode of the compound and GR was predicted by molecular docking. Anti-inflammatory activity evaluation; 2) According to preliminary structure-activity relationship, order or synthesize compounds. The specific implementation is as follows:
[0122] Wherein, the substituent R=-CH at any position on the benzene ring 3 , -F, -OCH 3
[0123] Obtainment of 6-nitro-1,2,3,4-tetrahydroquinoline:
[0124] 6-Nitroquinoline (1.74 g, 10 mmol), Hantatzsch ester (6.33 g, 25.0 mmol) and B(OH) 3 (123.6 mg, 2.0 mmol) was placed in a 250 mL single-neck bottle, and 100 mL of dichloroethane DCE was added as a solvent. The reaction was heated to 60°C overnight. After spotting the disappe...
Embodiment 3
[0206] Example 3: Evaluation of HP-19 Based Analog Activity
[0207] Taking HP-19 as the lead compound, we obtained a total of 24 compounds. As shown in Tables 1 and 2, the transcriptional inhibitory activity of most compounds against NF-kb was greater than 50% at 10 μM dosing. For N-phenylsulfonamide compounds, only one HP-26 (ChemDiv ID: V016-8573) was purchased due to fewer skeleton types in the compound library. The activity evaluation is as follows:
[0208]
[0209] Table 1 Inhibitory activity of N-phenylsulfonamide compounds (1) on NF-κB transcription level
[0210]
[0211]
[0212]
[0213]
[0214] Table 2 Inhibitory activity of N-phenylsulfonamide compounds (2) on NF-κB transcription level
[0215]
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Abstract
The invention discloses a sulfonamide compound and application thereof in preparation of a medicine for treating autoimmune diseases, and belongs to the technical field of medicines. The sulfonamide compound is any one of compounds or pharmaceutically acceptable salts thereof as shown in structural formulas (I)-VI, and the compound has glucocorticoidreceptor binding activity, can target a glucocorticoidreceptor ligand structural domain, effectively inhibits activation of downstream pro-inflammatory signal channels such as NF-kB and AP1, and can be used for preparing a medicine for preventing and treating tumors. The compound has a remarkable anti-inflammatory effect, cannot induce transcriptional activation, and cannot generate side effects caused by transcriptional activation; in addition, the compound has no cytotoxicity and has no binding activity to other steroidal nuclear receptors. Therefore, when being used as a glucocorticoidreceptorsmall moleculeregulator to be applied to the autoimmune diseases mediated by the glucocorticoid receptor, the glucocorticoid receptorsmall moleculeregulator provides a new treatment strategy and method for clinic.
Description
technical field [0001] The invention relates to the technical field of medicine, in particular to the application of sulfonamide compounds with glucocorticoid receptor binding activity in the preparation of glucocorticoid receptor small molecule regulators. Background technique [0002] Glucocorticoids (GCs) are widely used in clinical anti-inflammatory drugs for the treatment of asthma, psoriasis and other inflammatory diseases. GCs mainly exert their therapeutic effects through the glucocorticoid receptor (GR). But long-term glucocorticoid use is limited by serious side effects, manifested in hypertension and major metabolic side effects such as glucose intolerance, musclewasting, skinthinning, and osteoporosis. [0003] Current studies have shown that the anti-inflammatory mechanism of glucocorticoids is: GR that is not activated by GCs binds to binding proteins such as HSP90 in the cytoplasm. When bound to GCs, the conformation of GR LBD changes, GRα releases HSP, ente...
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