CN113101291A - Application of sulfonamide compound in preparation of medicine for treating autoimmune diseases - Google Patents
Application of sulfonamide compound in preparation of medicine for treating autoimmune diseases Download PDFInfo
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- CN113101291A CN113101291A CN202110401818.4A CN202110401818A CN113101291A CN 113101291 A CN113101291 A CN 113101291A CN 202110401818 A CN202110401818 A CN 202110401818A CN 113101291 A CN113101291 A CN 113101291A
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Abstract
The invention discloses an application of sulfonamide compounds in preparation of drugs for treating autoimmune diseases, and belongs to the technical field of medicines. The sulfonamide compound is a compound shown in structural formulas (I) - (VI) or any one of pharmaceutically acceptable salt, prodrug, stereoisomer, deuteron and solvate thereof, has glucocorticoid receptor binding activity, can target a glucocorticoid receptor ligand domain, effectively inhibits activation of multiple pathways such as downstream proinflammatory signal pathways NF-kB and AP1, has a remarkable anti-inflammatory effect, cannot induce transcription activation, and cannot generate side effects caused by transcription activation; in addition, the compound has no cytotoxicity and no binding activity to other steroid nuclear receptors, so that the compound is applied to the treatment of autoimmune diseases mediated by glucocorticoid receptors as a glucocorticoid receptor small molecule regulator.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of sulfonamide compounds with glucocorticoid receptor binding activity in preparation of glucocorticoid receptor small molecule regulators.
Background
Glucocorticoids (GCs) are the most widely used anti-inflammatory drugs for the treatment of a variety of inflammatory conditions such as asthma, psoriasis, etc., and they exert their therapeutic effects primarily through the Glucocorticoid Receptor (GR). However, long-term use of glucocorticoids is limited by serious side effects manifested by hypertension and major metabolic side effects such as glucose intolerance, muscle atrophy, skin thinning and osteoporosis.
Current studies indicate that the anti-inflammatory mechanism of glucocorticoids is: GR that is not activated by GCs binds to a binding protein such as HSP90 in the cytoplasm, and with GCs binding, GR LBD conformationally changes, and GR α releases HSP into the nucleus by means of ligand binding, and functions as a transcription factor to activate or inhibit transcription of downstream genes. Once inside the nucleus, GR binds to the GRE response element in a homodimeric form, i.e. (+) GRE dna, resulting in transcriptional expression of the gene, a pathway known as GR transcriptional activation. Since the GRE transcription activation pathway is involved in human glycometabolism, skeletal and endocrine functions, it is currently considered to be the main cause of side effects of GCs drugs. Simultaneously GCs binding can also cause direct and indirect transcriptional repression of GR: GCs-induced direct transcriptional repression is direct ligand-activated GR binding to evolutionarily conserved (-) GRE [ Inverted Repeat (IR) nGRE ]; indirect transcriptional inhibition, also known as "thermal transpression", is the decrease in production of cytokines, chemokines, adhesion factors, matrix metalloproteinases, cyclooxygenase-2 (COX-2), and the like, associated with inflammatory diseases, caused by interference with downstream pro-inflammatory signaling pathways by binding to specific factors such as (NF- κ B (p65), AP1(c-jun), or STAT3) in a manner that does not bind directly to DNA. It is generally believed that the anti-inflammatory effects of GCs are associated with indirect transcriptional repression, while direct transcriptional repression and direct transcriptional activation are associated with side effects.
In order to reduce the side effects of GCs, direct targeting of GR only results in transcriptional repression of GR, i.e. the search for small molecule modulators with no transcriptional activation and significant anti-inflammatory effects is one of the current important options for treating patients with inflammatory infections. Drug design targeting GR α has been highly successful. Structurally, GR consists of 777 amino acid residues, divided into 4 major domains, the N-terminal domain (NTD), the DNA Binding Domain (DBD), the hinge region and the C-terminal domain (ligand binding domain, LBD), respectively. Recent research has focused on the development of partial agonists or selective glucocorticoid receptor modulators that activate the inflammation inhibitory pathway but avoid targeting pathways that cause GC-related side effects.
Several compounds having glucocorticoid receptor modulating activity have been identified so far, and for example, patent document CN 112236416 a discloses a pyrimidinylcyclohexenyl compound as a glucocorticoid receptor modulator for use in the treatment of inflammatory diseases. Patent documents CN111556867A and CN 111491931 a disclose that substituted pyrrolidine amides are useful as glucocorticoid receptor modulators for the treatment and/or prevention of disorders mediated by the glucocorticoid receptor. The development of more novel compounds that effectively target the glucocorticoid receptor with fewer side effects to expand clinical drug options is a problem that needs to be addressed by those skilled in the art.
Disclosure of Invention
The invention aims to provide a small molecule compound with glucocorticoid receptor binding activity, which is used as a small molecule regulator targeting a glucocorticoid receptor and is used for treating autoimmune diseases, such as asthma, rheumatoid arthritis, psoriasis, inflammation and the like.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides an application of a compound with structural formulas shown in formulas (I) to (VI) or any one of pharmaceutically acceptable salt, prodrug, stereoisomer, deuteron and solvate thereof in preparing a medicament for treating autoimmune diseases,
wherein,
R1、R2and R3Each independently of the others is hydrogen, halogen, cyano, nitro, SF5SCN, amino, C1-C6Alkylamino, bis (C)1-C6) Alkylamino, hydroxy, carboxy, C1-C8Alkyl radical, C3-C6Cycloalkyl radical, C5-C7Cycloalkenyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C6Halogenocycloalkoxy, C1-C6alkyl-C3-C6Halogenocycloalkoxy, C1-C6alkyl-C1-C6Alkoxy radical, C1-C6alkyl-C1-C6Haloalkoxy, C1-C6alkoxy-C1-C6Alkoxy radical, C1-C6Alkyl-cyano, C1-C6alkyl-C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkenyloxy radical, C2-C6Alkynyl, C2-C6Alkynyloxy, SH, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonylalkyl, C1-C6Halogenated sulfonylalkyl, C1-C6alkyl-C1-C6Alkoxyamino group, C1-C6Alkylcarbonyl group, C3-C6Cycloalkyl carbonyl group, C1-C6Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl, C1-C6Alkylaminocarbonyl, bis (C)1-C6) Alkylaminocarbonyl, five-or six-membered aryl, five-or six-membered heteroaryl, C1-C6Alkyl-five-or six-membered aryl, five-or six-membered arylaminocarbonyl, five-or six-membered aryl-C1-C6Alkyl radical, C1-C6Alkyl-five-or six-membered heteroaryl, five-or six-membered heteroaryl-C1-C6Alkyl, five-or six-membered arylcarbonyl, five-or six-membered arylamido, five-or six-membered heteroarylcarbonyl, five-or six-membered heteroarylamido, five-or six-membered heteroarylaminocarbonyl, five-or six-membered heterocycle, C1-C6Alkyl-five-or six-membered heterocyclic group, five-or six-membered heterocyclic group-C1-C6Alkyl, five-or six-membered heterocyclylcarbonyl, five-or six-membered heterocyclylaminocarbonyl, an octato fourteen-membered heteroaromatic bicyclic or tricyclic ring system, C1-C6Alkyl-octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems, octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems-C1-C6Alkyl, octa-to deca-quaternary hetero-aryl bi-or tricyclic ring system based carbonyl, octa-to deca-quaternary hetero-aryl bi-or tricyclic ring system based amido, octa-to deca-quaternary hetero-aryl bi-or tricyclic ring system based aminocarbonyl;
or C1-C6Alkylamino, bis (C)1-C6) Alkylamino radical, C1-C8Alkyl radical, C3-C6Cycloalkyl radical, C5-C7Cycloalkenyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C6Halogenocycloalkoxy, C1-C6alkyl-C3-C6Halogenocycloalkoxy, C1-C6alkyl-C1-C6Alkoxy radical, C1-C6alkyl-C1-C6Haloalkoxy, C1-C6alkoxy-C1-C6Alkoxy radical, C1-C6Alkyl-cyano, C1-C6alkyl-C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkenyloxy radical, C2-C6Alkynyl, C2-C6Alkynyloxy, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonylalkyl, C1-C6Halogenated sulfonylalkyl, C1-C6alkyl-C1-C6Alkoxyamino group, C1-C6Alkylcarbonyl group, C3-C6Cycloalkyl carbonyl group, C1-C6Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl, C1-C6Alkylaminocarbonyl, bis (C)1-C6) Alkylaminocarbonyl, five-or six-membered aryl, five-or six-membered heteroaryl, C1-C6Alkyl-five-or six-membered aryl, five-or six-membered arylaminocarbonyl, five-or six-membered aryl-C1-C6Alkyl radical, C1-C6Alkyl-five-or six-membered heteroaryl, five-or six-membered heteroaryl-C1-C6Alkyl, five-or six-membered arylcarbonyl, five-or six-membered arylamido, five-or six-membered heteroarylcarbonyl, five-or six-membered heteroarylamido, five-or six-membered heteroarylaminocarbonyl, five-or six-membered heterocycle, C1-C6Alkyl-five-or six-membered heterocyclic group, five-or six-membered heterocyclic group-C1-C6Alkyl, five-or six-membered heterocyclylcarbonyl, five-or six-membered heterocyclylaminocarbonyl, an octato fourteen-membered heteroaromatic bicyclic or tricyclic ring system, C1-C6Alkyl-octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems, octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems-C1-C6Alkyl, octa-to deca-quaternary heteroaromatic bicyclic or tricyclic ring system carbonyl, octa-to deca-quaternary heteroaromatic bicyclic or tricyclic ring system amido, octa-to deca-quaternary heteroaromatic bicyclic or tricyclic ring system aminocarbonylBy hydrogen, halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy or C1-C6Thioalkyl mono-or polysubstituted;
p is 1, 2 or 3;
z is O, N or C;
A1，A2each independently is H, C, CR1O, S or NR1Or form a ring-merged structure I with a benzene ring and consecutive atoms
Or the fused ring structure I is substituted by at least one R1Substituted;
Q1，Q2each independently is H, C, CR1O, S or NR1Or form a ring-merged structure with Z and the successive atoms II
Or the said fused ring structure II is substituted by at least one R1And (4) substituting.
Preferably, R1Is amino, halogen, C1-C8Alkyl radical, C1-C6Alkylcarbonyl group, C3-C6Cycloalkyl carbonyl group, C1-C6Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl, C1-C6Alkylaminocarbonyl, bis (C)1-C6) An alkyl amino carbonyl group,
or amino, C1-C8Alkyl radical, C1-C6Alkylcarbonyl group, C3-C6Cycloalkyl carbonyl group, C1-C6Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl, C1-C6Alkylaminocarbonyl, bis (C)1-C6) By hydrogen, halogen, cyano, nitro radicals of alkylaminocarbonyl radicalsRadical, hydroxy radical, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy or C1-C6Thioalkyl groups are mono-or polysubstituted.
More preferably, R1Is halogen, C1-C8An alkyl group. Halogen, C1-C8The alkyl group may be substituted by hydrogen, halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy or C1-C6Thioalkyl groups are mono-or polysubstituted.
Preferably, Z is C or N.
More preferably, Z is N.
Preferably, p is 2 or 3.
More preferably, p is 3.
Preferably, R2And R3Is H and a substituted benzo ring.
Said substituted benzo ring is
Preferably, A1，A2Is composed of
More preferably, A1，A2Is composed of
Preferably, Z, Q1，Q2The substituted piperidine, the substituted indoline and the substituted piperazine are formed together.
More preferably, Z, Q1，Q2Are composed of
Preferably, the compound has the following structural formula:
the research of the invention shows that the compound has high selectivity on a targeted glucocorticoid receptor, effectively inhibits the activation of multiple pathways such as downstream proinflammatory signal pathways NF-kB, AP1 and the like, has obvious anti-inflammatory effect and can reduce the generation of side effects. Namely, the action mechanism of the compound is as follows: the compound has glucocorticoid receptor binding activity, and inhibits NF-kB signal path and/or AP1 signal path by targeting glucocorticoid receptor, thereby reducing the expression of inflammatory factors. Thus, the compounds may be used as glucocorticoid receptor modulators for the treatment of disorders mediated by the glucocorticoid receptor.
Further, the autoimmune disease is asthma, rheumatoid arthritis, psoriasis, inflammation.
Description of terms: "alkyl" refers to a straight or branched hydrocarbon chain comprising 1 to 6 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and substituted alkyl. The alkyl groups described herein may optionally be substituted one or more times with halogen or hydroxy. Thus, the term "alkyl" also includes, for example, trifluoromethyl as well as other haloalkyl groups, hydroxymethyl groups, and other hydroxylated alkyl groups as specified.
"alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and substituted alkoxy. The alkoxy groups described herein may optionally be substituted one or more times with halogen.
"aromatic ring" refers to an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms having a completely conjugated pi-electron system. Non-limiting examples of aryl groups are: benzene ring, naphthalene ring, anthracene ring.
"aromatic heterocycle" refers to a non-all carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms having a completely conjugated pi-electron system. Non-limiting examples of aryl groups are: pyridine, imidazole, furan, thiazole, purine, indole, thiophene and azaindole.
"cycloalkyl" refers to a saturated carbocyclic ring of 3 to 8 ring atoms, examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
"halogen" means fluorine, chlorine, bromine or iodine.
"pharmaceutically acceptable salts" include alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkanesulfonic acid salts, arylsulfonic acid salts, organic acid salts, amino acid salts.
Preferably, the pharmaceutically acceptable salt is hydrochloride, benzenesulfonate, methylbenzenesulfonate, phosphate, maleate, sulfate, acetate, citrate, fumarate or tartrate.
The medicament also comprises a pharmaceutically acceptable carrier. The "pharmaceutically acceptable carrier" refers to a pharmaceutical carrier which is conventional in the pharmaceutical field and includes diluents, excipients such as water and the like, fillers such as starch and the like, binders such as cellulose derivatives, gelatin and the like, humectants such as glycerin, disintegrating agents such as agar-agar, calcium carbonate and the like, adsorptive carriers such as kaolin and bentonite, surfactants such as cetyl alcohol, absorption promoters such as quaternary ammonium compounds, lubricants such as talc and the like, and flavoring agents, sweeteners and the like may be added as necessary.
The pharmaceutical formulations are adapted for administration by any suitable route, for example by nasal spray, oral spray (inhalation), oral (including buccal or sublingual), rectal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. The pharmaceutical preparation of the present invention can be prepared by any method known in pharmacy. For example, by admixing the active ingredient with a carrier or excipient.
The invention has the following beneficial effects:
the compound provided by the invention has glucocorticoid receptor binding activity, can target a glucocorticoid receptor ligand domain, effectively inhibits activation of multiple pathways such as downstream proinflammatory signal pathways NF-kB, AP1 and the like, 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 no binding activity to other steroid nuclear receptors, so that the compound has potential application value in the treatment of autoimmune diseases mediated by glucocorticoid receptors.
Drawings
Figure 1 shows the structure and anti-inflammatory activity of the compounds found in the virtual screening.
FIG. 2 shows the transcriptional repression of NF-kb by the compounds HP-19 and dexamethasone (Dex).
FIG. 3 shows the results of the compounds with significant anti-inflammatory activity binding to glucocorticoid receptor strongly and weakly at 10. mu.M.
FIG. 4 is a test of the binding activity of compounds on GR LBD.
FIG. 5 shows the transcriptional repression of AP-1 by the compounds HP-19 and dexamethasone (Dex).
FIG. 6 is an evaluation of the compounds HP-19 and dexamethasone (Dex) for GR transcriptional activation.
FIG. 7 is an evaluation of GR transcriptional antagonism by compounds HP-19, mifepristone (RU486) and Azd 9567.
FIG. 8 shows the effect of qPCR detection of HP-19 on GR endogenous target gene expression.
FIG. 9 shows the safety evaluation of compound HP-19.
FIG. 10 shows the selectivity of compound HP-19 for Androgen Receptor (AR).
FIG. 11 is the selectivity of compound HP-19 for the Progestin Receptor (PR).
Detailed Description
The present invention will be further described with reference to the following specific examples.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
Virtual screening based on structure
The experimental principle is as follows: and (3) predicting the binding mode and the binding free energy between the compounds in the compound database and the glucocorticoid receptor by using virtual screening based on the structure, and screening the small-molecule compounds capable of binding with the glucocorticoid receptor.
The experimental method comprises the following steps: based on the crystal structure of a glucocorticoid receptor (PDB number: 6EL9), a Glide molecular docking module of a Schrodinger molecular simulation software package is adopted to perform virtual screening based on the structure on a chemdiv small molecule database, 3000 optimal compounds are scored for conformation analysis, and 88 compounds are finally purchased for activity screening.
The experimental results are as follows: the 24 potential glucocorticoid analogues were screened and possessed different chemical backbones (fig. 1).
Second, glucocorticoid receptor anti-inflammatory ability evaluation experiment
The detection principle is as follows: because glucocorticoids exert anti-inflammatory effects, the reduction in the expression of inflammatory factors is mainly caused by the transcriptional repression pathway, i.e., inhibition of NF-. kappa.B (p65) and AP1(c-jun) signaling pathways. The dual-luciferase reporter gene test system is sensitive, is used for measuring two independent luciferase reporter genes, namely firefly luciferase and ocean Renilla luciferase, in one system, and the ocean Renilla luciferase has stable expression in different types of mammalian cells and insensitive expression activity to external drug stimulation, and can be used for correcting errors caused by different transfection efficiencies. Thus, in the dual luciferase reporter assay, Renilla luciferase provides for normalization of the experimental reporter Firefly luciferase assay test as a control reporter; when the inhibitory activity of the compound to be tested on NF-kappa B or AP-1 is higher, the smaller the relative ratio of Fireflyfluenase/Renilla luciferase is, the stronger the anti-inflammatory capability of the compound is measured.
A detection step: in the detection method of the present invention, (Hela) in the cervical cancer cell is expressed at 1X 104The density of individual/well was seeded into clear 96-well plates. After cells were stably attached, Hela was co-transfected with human full-length GR alpha protein, pNF-. kappa.B-luc and Rencilla (pRL-TK) using Lipofectamine 3000. 24h after transfection, cells were treated with 5ng/ml TNF α and 10 μ M test compound, respectively. After 18h, the cell culture plate was removed, washed 2 times with PBS, the waste solution was discarded, and 20. mu.l of 1 XPLB lysate (Passive Lysis Buffer) was added to each well, 30. mu.l per well. The cell culture plate was placed on a shaker for sufficient lysis for 30 minutes. The relative luciferase content in each well was measured using a microplate reader and obtained as Firefly luciferase/Renilla luciferase.
And (3) detection results: the transcriptional repression activity of the compounds on NF-kb upon administration of 10. mu.M is shown in FIG. 1. The transcription inhibition activity of HP-21, HP-30, HP-49 and HP-57 with benzene sulfonamide structure on NF-kb is more than 50% under the concentration of 10 mu M. Wherein HP-49 has better transcription inhibition activity of NF-kb, IC500.256 μ M. HP-7 with N-phenylsulfonamide also has good transcription inhibition activity, IC, on NF-kb50＝0.17μM。
Of all 24 compounds, compounds having N-phenylbenzenesulfonamide (e.g., HP-5, HP-11, HP-12, HP-14, HP-18, HP-19, HP-23, HP-25, HP-28, HP-29, HP-31, HP-39, and HP-40) exhibited the best anti-inflammatory activity.
As shown in FIG. 2, HP-19 had the strongest NF- κ B inhibitory activity among the test compounds, its IC5041nM, with the positive compound dexamethasone (IC)5012nM) are of the same order of magnitude.
Selecting small molecules with transcription inhibition activity of more than 50%, and further determining the IC50Values were used for next target validation.
Third, glucocorticoid receptor competitive binding experiment verifies and target binding strength
The detection principle is as follows: the binding ability of the compounds to the glucocorticoid receptor was examined using time-resolved fluorescence resonance energy transfer (TR-FRET) technique by Invitrogen. When proceeding with
Fluormone in a TR-FRET GR competitive binding assayTMGS1 Green tracer was added to the ligand test compound or solvent control, followed by a mixture of GR-LBD (GST) and Tb-anti-GST antibodies. After incubation for 2h at room temperature, readings are taken at 520nm and 495nm, respectively, and the TR-FRET ratio value (ratio) is calculated to be 520:495, which can be used to determine IC from dose response curves of compounds50. If the test compound competes for the ligand, it will compete for the ligand in the ternary complex, causing the ratio value to decrease. Instead of targeting the site, the value remains at the original level. By utilizing the principle, the target binding capacity of the compound to the glucocorticoid receptor can be quantitatively determined.
A detection step: mixing a mixture of glucocorticoid receptor ligand binding domain { GR-LBD (His-GST) } and Tb-anti-GST antibody with the compounds to be tested with different concentration gradients, and adding fluorescent ligand (Fluormone)TMGS1 Green) with 10 μ M dexamethasone as positive control. And (3) detecting the change of the ratio by using a multifunctional enzyme-labeling instrument, and quantitatively determining whether the compound with high antagonistic activity accurately targets the glucocorticoid receptor.
And (3) detection results: as shown in FIG. 3, at a compound concentration of 10. mu.M, HP-1, HP-6, HP-19, HP-24, HP-26 and HP-67 all exhibited a high ability to target the glucocorticoid receptor ligand domain. Furthermore, compounds HP-19, HP-24 and HP-67 with strong anti-inflammatory effects are selected for concentration gradient detection. As shown in FIG. 4, compounds HP-19, HP-24 and HP-67 are concentration dependent, indicating that compounds HP-19, HP-24 and HP-67 correctly target the glucocorticoid receptor ligand domain and exert anti-inflammatory effects.
Evaluation experiment of AP-1 signal pathway inhibition by compound
The detection principle is as follows: because glucocorticoids exert anti-inflammatory effects, the reduction in the expression of inflammatory factors is mainly caused by the transcriptional repression pathway, i.e., inhibition of NF-. kappa.B (p65) and AP1(c-jun) signaling pathways. Thus, in the dual luciferase reporter assay, Renilla luciferase provides for normalization of the experimental reporter Firefly luciferase assay test as a control reporter; when the inhibitory activity of the compound AP-1 to be detected is higher, the smaller the relative ratio of Fireflyfluenase/Renilla luenase is, the stronger the anti-inflammatory ability of the compound is detected.
A detection step: in the detection method of the present invention, (Hela) in the cervical cancer cell is expressed at 1X 104The density of individual/well was seeded into clear 96-well plates. After the cells were stably attached, HeLa was co-transfected with human full-length GR alpha protein, 5 Xap-1-luc and Rencilla (pRL-TK) using Lipofectamine 3000. 24h after transfection, cells were treated with 1ng/ml PMA (for the AP-1 reporter system) and different concentration gradients of test compound. After 18h, the cell culture plate was removed, washed 2 times with PBS, the waste solution was discarded, and 20. mu.l of 1 XPLB lysate (Passive Lysis Buffer) was added to each well, 30. mu.l per well. The cell culture plate was placed on a shaker for sufficient lysis for 30 minutes. The relative luciferase content in each well was measured using a microplate reader and obtained as Firefly luciferase/Renilla luciferase.
And (3) detection results: as shown in FIG. 5, compound HP-19 has good AP-1 inhibitory activity, its IC50790nM indicates that the compound has a better anti-inflammatory effect.
Fifth, evaluation experiment of GR transcriptional Activity by Compounds
5.1 evaluation of Compounds on GR transcriptional activation
The detection principle is as follows: we constructed a cell line Hela-MMTV-luc based on Hela cells, in which the activity of firefly luciferase is dependent on the promoter MMTV (glucocorticoid receptor response element is contained in MMTV promoter and reported in literature, which is one of the models for detecting the transcription activation activity). The expression condition of luciferase in Hela-MMTV-luc directly reflects the strength of GR exerting the activity of transcription factors. GR transcriptional activation activity of the compound at the cellular level can be quantified by measuring the intensity of luciferase expression in Hela-MMTV-luc. For compounds with good transcriptional activation activity, we performed concentration gradient detection on the compounds and calculated IC50The value is obtained.
A detection step: Hela-MMTV-luc cells were cultured in complete hormone-free medium for 2 days at 1X 104Density of individual/well was seeded into opaque white 96-well plates. After the cells are stably attached to the wall, compounds with different concentration gradients and dexamethasone are given, after incubation for 24 hours, chemiluminescence is detected by using a multifunctional enzyme-labeling instrument, and the transcription activation activity (IC) of the compounds is quantitatively calculated50) The positive drug dexamethasone was used as a control.
And (3) detection results: as shown in FIG. 6, compound HP-19 did not induce transcriptional activation at any concentration, whereas dexamethasone had a strong transcriptional activation. This result suggests that compound HP-19 may not cause side effects due to transcriptional activation.
5.2 evaluation of GR transcriptional antagonism by Compounds
The detection principle is as follows: since transcriptional activation is currently considered to be the main cause of side effects caused by long-term clinical use of steroid drugs, it is possible to overcome side effects caused by long-term administration if the compound has no transcriptional activation activity or has an inhibitory effect on agonistic activity caused by dexamethasone. Therefore, detecting whether a compound antagonizes GR transcriptional activation is an important indicator for overcoming side effects. Quantification can be achieved by determining whether the compound can reduce the luciferase activity in the dexamethasone-induced Hela-MMTV-luc cellsThe GR transcriptional antagonistic activity of the compound at the cellular level. For the compound with good transcription antagonistic activity, we performed concentration gradient detection and calculated IC50The value is obtained.
A detection step: Hela-MMTV-luc at 1X 104Density of individual/well was seeded into opaque white 96-well plates. After cells are stably attached to the wall, a compound which is induced by 100nM dexamethasone and has different concentration gradients is given, after incubation for 24 hours, chemiluminescence is detected by a multifunctional microplate reader, and the transcription antagonistic activity (IC) of the compound is quantitatively calculated50) The positive drug mifepristone is used as a control.
And (3) detection results: as shown in FIG. 7, compound HP-19 failed to antagonize the transcriptional activation induced by dexamethasone at any concentration, whereas GR antagonist and small molecule modulator both demonstrated greater transcriptional antagonism of Azd 9567. HP-19 may be a small molecule modulator with a novel anti-inflammatory mechanism.
Sixthly, expression of glucocorticoid receptor protein target gene inflammatory factor
The detection principle is as follows: GR regulates the target gene negatively through a transcription inhibition mechanism, typical target genes comprise a large number of inflammatory proteins such as IL-1 beta, IL-6, IL-8, IL-12, cyclooxygenase 2(COX-2) and the like, GR regulates the target gene positively through a transcription activation mechanism, and GILZ is one of the earliest reported genes induced by GCR transcription activation. To confirm that the activity of compound HP-19 does not result in a false positive, the anti-inflammatory activity of the compound was evaluated by testing the effect of the compound on the expression of the glucocorticoid receptor endogenous target gene at the mRNA level.
A detection step: the effect of the compound on the expression of the glucocorticoid receptor endogenous target gene is detected at the mRNA level by a quantitative PCR (qPCR) method. RAW264.7 cells were cultured in 6-well plates containing 5% charcoal/dextran treated fetal bovine serum (CSS) medium. After 48 hours of treatment, mRNA was extracted using the EZ-10 DNAway RNA Mini-Preps kit and reverse transcribed to cDNA. Use of
III 1st cDNA Supermix for qPCR, Final AccessAmplification was performed by qPCR SYBR Green Master Mix.
And (3) detection results: as shown in FIG. 8, compound HP-19 can significantly reduce the mRNA level of IL-6 beta and COX-2, but has no effect on the mRNA expression level of IL-1 beta, and consistent with the results of the transcriptional activation experiment, the compound does not affect the mRNA expression level of the target gene GILZ with transcriptional activation, and indirectly indicates that the compound may reduce the generation of side effects.
Seventhly, the safety of the compound HP-19 is detected by an MTT method
The detection principle is as follows: in order to determine whether the compound is cytotoxic, the invention uses normal mouse embryo fibroblast (NIH-3T3) for toxicity test to determine its safety.
The experimental steps are as follows: using complete medium at 5X 103NIH-3T3 cells were seeded at a density per well in 96-well plates. After cell attachment, the cells were incubated at 37 ℃ for 24 hours, then treated with varying concentrations of compound HP-19 and incubated for an additional 48 hours. Thereafter, 10. mu.L of 5mg/ml MTT was added to each well and incubated for 4 hours. Then 100. mu.L of SDS-HCl-PBS triple buffer was added to each well and incubated overnight at 37 ℃. Finally, detecting the absorbance value of each hole at 570nm under a microplate reader, and converting the absorbance value into the survival rate.
The experimental results are as follows: as shown in FIG. 9, the compound HP-19 has the same safety level as the positive drug dexamethasone at NIH-3T3, and the proliferation of cells is not inhibited by 50uM even at high concentration. The above results show that the compound HP-19 of the present invention has high safety.
Eighthly, detecting the selectivity of the compound for other nuclear receptors
The detection principle is as follows: to test whether a compound is selective for other steroidal nuclear receptors such as Androgen Receptor (AR) and Progestin Receptor (PR), we tested AR and PR using the constructed LNCaP-ARR2PB-EGFP cell model and dual luciferase reporter system, respectively.
For the detection principle of AR: androgen Receptor (AR) is a transcription factor that requires binding to a specific sequence to exert its transcriptional activity. In the detection method, reporter gene Enhanced Green Fluorescent Protein (EGFP) controlled by an ARR2PB promoter is introduced into androgen receptor dependent prostate cancer cells (LNCaP), so that the LNCaP cells express an EGFP prostate cancer cell line (LNCaP-ARR2PB-EGFP) regulated by androgen receptors. After treatment by different concentration gradient test compounds, the expression level of EGPF in LNCaP-ARR2PB-EGFP cells is detected, and the strength of the transcriptional activation capability of the compounds on androgen receptors can be measured.
A detection step: LNCaP-ARR2PB-EGFP cells were first cultured for several days in complete androgen-free medium and background fluorescence was measured. After the fluorescence value decreased to a lower level, it was measured at 3.5X 104The density of individual/well was seeded into black bottom-penetrating 96-well plates. After cells are stably attached to the wall, Dihydrotestosterone (DHT) and a compound are given for induction, after incubation for 24-48 hours, a multifunctional microplate reader is adopted to detect the fluorescence intensity value near 530nM wavelength under excitation light with the wavelength of 485nM, and a positive drug of 10nM Dihydrotestosterone (DHT) is used as a control.
Detection principle for PR: the Progestagen Receptor (PR) is a transcription factor that requires binding to a specific sequence to exert its transcriptional activity. It was found that PR binds to the ARR3tk promoter and causes transcription of downstream genes. In the detection method for evaluating PR, ARR3tk-luc and Rencilla are co-transfected in a prostate cancer cell line PC3 and are corrected by taking the Rencilla as an internal reference plasmid, and data measured by using a dual-luciferase reporter gene principle
A detection step: in the detection method of the present invention, the prostate cell line PC3 was used at 1X 104The density of individual/well was seeded into clear 96-well plates. After the cells were stably attached to the wall, the human full-length PR α protein, 3 xar 3tK-luc and Rencilla were co-transfected with PC3 using Lipofectamine 3000. 24h after transfection, cells were treated with different concentrations of HP-19, with 10ng/ml of progestogen as a control. After 18h, the cell culture plate was removed, washed 2 times with PBS, the waste solution was discarded, and 20. mu.l of 1 XPLB lysate (Passive Lysis Buffer) was added to each well, 30. mu.l per well. The cell culture plate was placed on a shaker for sufficient lysis for 30 minutes. The relative luciferase content in each well was measured using a microplate reader and obtained as Firefly luciferase/Renilla luciferase.
The experimental results are as follows: as shown in FIGS. 10 and 11, compound HP-19 did not cause transcriptional activation of AR and PR, while the positive drug dexamethasone had some transcriptional activation of both AR and PR. Dexamethasone is poorly selective for other nuclear receptors and is also a cause of side effects. Therefore, the results show that the compound HP-19 has better selectivity of AR and PR nuclear receptors, and can avoid the side effects caused by off-target to a certain extent.
Example 2: HP-19 based analog screening
Taking HP-19 as a lead compound, and obtaining the analogue in two ways: 1) selecting analogues containing N-phenyl benzene sulfonamide from a Chemdiv compound library, predicting a binding mode of the compound and GR through molecular docking, and selecting the compound for anti-inflammatory activity evaluation; 2) ordering the compound according to the preliminary structure-activity relationship. Finally, 5 skeletons are obtained, the structural formulas are shown as (1) to (5), and 34 compounds are obtained. As shown in Table 1, Table 2, Table 3, Table 4 and Table 5, most of the compounds exhibited a transcription inhibitory activity of more than 50% for NF-kb upon administration at 10. mu.M.
TABLE 1 inhibitory Activity of N-phenylsulfonamide Compounds (1) on NF- κ B transcription level
TABLE 2 inhibitory Activity of N-phenylsulfonamide Compound (2) on NF- κ B transcription level
TABLE 3 inhibitory Activity of N-phenylsulfonamide Compound (3) on NF- κ B transcription level
TABLE 4 inhibitory Activity of N-phenylsulfonamide Compound (4) on NF- κ B transcription level
TABLE 5 inhibitory Activity of N-phenylsulfonamide Compound (5) on NF- κ B transcription level
The description of the embodiments is intended to explain the principles of the invention and to exemplify its practical application so that others skilled in the art can make implementations and modifications using the invention. The scope of the invention is defined by the claims and their equivalents.
Claims (10)
1. The application of any one of the compounds with the structural formulas shown in formulas (I) to (VI) or pharmaceutically acceptable salts, prodrugs, stereoisomers, deuterons and solvates thereof in preparing the medicine for treating autoimmune diseases,
wherein,
R1、R2and R3Each independently of the others is hydrogen, halogen, cyano, nitro, SF5SCN, amino, C1-C6Alkylamino, bis (C)1-C6) Alkylamino, hydroxy, carboxy, C1-C8Alkyl radical, C3-C6Cycloalkyl radical, C5-C7Cycloalkenyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C6Halogenocycloalkoxy, C1-C6alkyl-C3-C6Halogenocycloalkoxy, C1-C6alkyl-C1-C6Alkoxy radical, C1-C6alkyl-C1-C6Haloalkoxy, C1-C6alkoxy-C1-C6Alkoxy radical, C1-C6Alkyl-cyano, C1-C6alkyl-C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkenyloxy radical, C2-C6Alkynyl, C2-C6Alkynyloxy, SH, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonylalkyl, C1-C6Halogenated sulfonylalkyl, C1-C6alkyl-C1-C6Alkoxyamino group, C1-C6Alkylcarbonyl group, C3-C6Cycloalkyl carbonyl group, C1-C6Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl, C1-C6Alkylaminocarbonyl, bis (C)1-C6) Alkylaminocarbonyl, pentabasic orSix-membered aryl, five-or six-membered heteroaryl, C1-C6Alkyl-five-or six-membered aryl, five-or six-membered arylaminocarbonyl, five-or six-membered aryl-C1-C6Alkyl radical, C1-C6Alkyl-five-or six-membered heteroaryl, five-or six-membered heteroaryl-C1-C6Alkyl, five-or six-membered arylcarbonyl, five-or six-membered arylamido, five-or six-membered heteroarylcarbonyl, five-or six-membered heteroarylamido, five-or six-membered heteroarylaminocarbonyl, five-or six-membered heterocycle, C1-C6Alkyl-five-or six-membered heterocyclic group, five-or six-membered heterocyclic group-C1-C6Alkyl, five-or six-membered heterocyclylcarbonyl, five-or six-membered heterocyclylaminocarbonyl, an octato fourteen-membered heteroaromatic bicyclic or tricyclic ring system, C1-C6Alkyl-octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems, octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems-C1-C6Alkyl, octa-to deca-quaternary hetero-aryl bi-or tricyclic ring system based carbonyl, octa-to deca-quaternary hetero-aryl bi-or tricyclic ring system based amido, octa-to deca-quaternary hetero-aryl bi-or tricyclic ring system based aminocarbonyl;
or C1-C6Alkylamino, bis (C)1-C6) Alkylamino radical, C1-C8Alkyl radical, C3-C6Cycloalkyl radical, C5-C7Cycloalkenyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C3-C6Halogenocycloalkoxy, C1-C6alkyl-C3-C6Halogenocycloalkoxy, C1-C6alkyl-C1-C6Alkoxy radical, C1-C6alkyl-C1-C6Haloalkoxy, C1-C6alkoxy-C1-C6Alkoxy radical, C1-C6Alkyl-cyano, C1-C6alkyl-C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkenyloxy radical、C2-C6Alkynyl, C2-C6Alkynyloxy, C1-C6Thioalkyl, C1-C6Sulfinylalkyl radical, C1-C6Sulfonylalkyl, C1-C6Halogenated sulfonylalkyl, C1-C6alkyl-C1-C6Alkoxyamino group, C1-C6Alkylcarbonyl group, C3-C6Cycloalkyl carbonyl group, C1-C6Halogenoalkylcarbonyl group, C1-C6An alkoxycarbonyl group,
C1-C6Alkylaminocarbonyl, bis (C)1-C6) Alkylaminocarbonyl, five-or six-membered aryl, five-or six-membered heteroaryl, C1-C6Alkyl-five-or six-membered aryl, five-or six-membered arylaminocarbonyl, five-or six-membered aryl-C1-C6Alkyl radical, C1-C6Alkyl-five-or six-membered heteroaryl, five-or six-membered heteroaryl-C1-C6Alkyl, five-or six-membered arylcarbonyl, five-or six-membered arylamido, five-or six-membered heteroarylcarbonyl, five-or six-membered heteroarylamido, five-or six-membered heteroarylaminocarbonyl, five-or six-membered heterocycle, C1-C6Alkyl-five-or six-membered heterocyclic group, five-or six-membered heterocyclic group-C1-C6Alkyl, five-or six-membered heterocyclylcarbonyl, five-or six-membered heterocyclylaminocarbonyl, an octato fourteen-membered heteroaromatic bicyclic or tricyclic ring system, C1-C6Alkyl-octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems, octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems-C1-C6Alkyl, octa-to deca-quaternary heteroaromatic bicyclic or tricyclic radical carbonyl, octa-to deca-quaternary heteroaromatic bicyclic or tricyclic radical amido, octa-to deca-quaternary heteroaromatic bicyclic or tricyclic radical aminocarbonyl, substituted by hydrogen, halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl radical, C1-C6Alkoxy radical, C1-C6HalogenatedAlkyl radical, C1-C6Haloalkoxy or C1-C6Thioalkyl mono-or polysubstituted;
p is 1, 2 or 3;
z is O, N or C;
A1，A2each independently is H, C, CR1O, S or NR1Or form a ring-merged structure I with a benzene ring and consecutive atoms
Or the fused ring structure I is substituted by at least one R1Substituted;
Q1，Q2each independently is H, C, CR1O, S or NR1Or form a ring-merged structure with Z and the successive atoms II
Or the said fused ring structure II is substituted by at least one R1And (4) substituting.
2. The use of claim 1, wherein R is1Is amino, halogen, C1-C8Alkyl radical, C1-C6Alkylcarbonyl group, C3-C6Cycloalkyl carbonyl group, C1-C6Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl, C1-C6Alkylaminocarbonyl, bis (C)1-C6) An alkyl amino carbonyl group,
or amino, C1-C8Alkyl radical, C1-C6Alkylcarbonyl group, C3-C6Cycloalkyl carbonyl group, C1-C6Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl, C1-C6Alkylaminocarbonyl, bis (C)1-C6) By hydrogen, halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6A cycloalkyl group, a,C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy or C1-C6Thioalkyl groups are mono-or polysubstituted.
3. The use of claim 1, wherein R is2And R3Is a combination of H and a substituted benzo ring,
said substituted benzo ring is
4. The use of claim 1, wherein Z, Q1，Q2The substituted piperidine, the substituted indoline and the substituted piperazine are formed together.
5. The use of claim 4, wherein Z, Q1，Q2Are composed of
6. The use of claim 1, wherein the compound has the formula:
7. the use of claim 1, wherein the compound has glucocorticoid receptor binding activity, inhibiting the NF- κ B signaling pathway and/or the AP1 signaling pathway by targeting the glucocorticoid receptor, thereby reducing inflammatory factor expression.
8. The use according to claim 7, wherein the autoimmune disease is asthma, rheumatoid arthritis, psoriasis, inflammation.
9. The use of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, benzenesulfonate, methylbenzenesulfonate, phosphate, maleate, sulfate, acetate, citrate, fumarate, or tartrate salt.
10. The use of claim 1, wherein the medicament further comprises a pharmaceutically acceptable carrier.
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