CN101108187A - Application of a compound in preparing anti-virus medicament - Google Patents
Application of a compound in preparing anti-virus medicament Download PDFInfo
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- CN101108187A CN101108187A CNA2006100291731A CN200610029173A CN101108187A CN 101108187 A CN101108187 A CN 101108187A CN A2006100291731 A CNA2006100291731 A CN A2006100291731A CN 200610029173 A CN200610029173 A CN 200610029173A CN 101108187 A CN101108187 A CN 101108187A
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Abstract
The invention relates to the technical field of chemical industry, in particular to a preparation method and application of micromolecule compound with HIV resisting activity. CyPA is able to combine with the Gag polymer protein in HIV-1. Silence or inhibit the activity of CypA with RNAi technology and disturb the replication of virus. The micromolecule compound in the invention refers to a CyPA inhibitor that has the effect of resisting HIV-1 virus. Besides, as the micromolecule compound is designed while aiming at cellular target, the invention is not easy to develop drug resistance, thus meeting the demands of lifetime medication for AIDS patients. Therefore, the micromolecule compound in the invention, which can be developed as a new type anti-AIDS drug, provides a new means for treating and curing AIDS.
Description
Technical field
The present invention relates to chemical field and field of medicaments, relate to the application of a kind of chemical compound in the preparation anti-AIDS drug.
Background technology
Cyclophilin Cycliphilins (CyPs) is the intracellular protein of widespread distribution, all exists in plant, antibacterial and mammal, has high conservative, is found as the cell receptor of ciclosporin A at first.(CyclosporinA is to separate 11 the amino acid whose ring type polypeptides that contain that obtain from fungus metabolite CsA) to ciclosporin A, is usually used in treating rejection and the autoimmune systemic disease that is produced after the organ transplantation clinically as immune suppressant drug.The CyPs that has at present found and cloned has more than 130 kind of isomer [GalatA.Metcalfe SM.Peptidyl proline cis-trans iso-merases.Prog Biophys Molec Biol, 1995; 63:67.], they have constituted Cyclophilins family.CyPs has peptide cis-trans propyl isomerism enzyme (PPIase) activity, the catalytic proteins folding process, especially the protein folding of proline rich, and play molecular chaperones effect [Ivery MT.Immunophilins:switched on protein binding domains? Med Res Rev.2000; 20 (6): 452-484.].Meanwhile, CyPs is relevant biological process such as apoptosis [the Lee JP of wide participation also, Palfrey HC, Bindokas VP, et al.The role of immunophilins in mutant superoxidedismutas-l linked familial amyotrophic lateral sclerosis.Proc Natl Acad Sci USA.1999; 96 (6): 3251-3256.] and intercellular signal conduction [Jin ZJ, Melaragno MG, Liao DF, et al.CyclophilinA is a secreted growth factor induced by oxidative stress.Circ Res.2000; 87 (9): 789-796.] etc.
Many studies show that arranged, and CyPA can combine with the Gag polyprotein (Gag polyprotein) of HIV (human immunodeficiency virus) (HIV-1).This combination makes CypA to be packaged into specifically in the HIV-1 virion, and be not wrapped into [Franke EK in other retrovirus, Yuan HE, Luban J.Specificincorporation of cyclophilin A into HIV-1 virions.Nature.1994; 372 (6504): 359-362.].In HIV-1 type virus self assembling process, CyPA enters virus as specific ingredient, commitment at the HIV-1 infection cell [the Braaten D that plays a role, Franke EK, Luban J.Cyclophilin A isrequired for an early step in the life cycle of human immunodeficiency virus type 1before the initiation ofreverse transcription.J Virol.1996; 70 (6): 3551-3560.].CypA and Gag make the N end CA domain that the site has been defined in Gag at present (this domain after the HIV-1 maturation through being cut into the p24 coat protein) mutually, the proline isomerase activity of CypA can be assisted the shell process of undressing [the Gamble TR after virus is finished infection cell, Vajdos FF, Yoo S, Worthylake DK, Houseweart M, Sundquist WI, Hill CP.Crystal structure of human cyclophilin A boundto the amino-terminal domain of HIV-1 capsid.Cell.1996; 87 (7): 1285-1294.].[as demonstrated by gene targeting in human T cells.EMBO J.2001 for Braaten D, Luban J.Cyclophilin A regulates HIV-1infectivity in the expression of the reticent CypA of use RNAi technology; 20 (6): 1300-1309; Sokolskaja E, Sayah DM, Luban J.Target cell cyclophilin Amodulates human immunodeficiency virus type 1 infectivity.J Virol.2004; 78 (23): 12800-12808.], perhaps use CsA and derivant thereof [Sokolskaja E, Sayah DM, Luban J.Target cell cyclophilin A modulates human immunodeficiency virus type 1 ingrctivity.JVirol.2004; 78 (23): 12800-12808.; Bartz SR, Hohenwalter E, Hu MK, Rich DH, Malkovsky M.Inhibition of human immunodeficiency virus replication bynonimmunosuppressive analogs of cyclosporin A.Proc Natl Acad Sci U S is A.1995; 92 (12): 5381-5385.; Steinkasserer A, Harrison R, Billich A, Hammerschmid F, Werner G.Wolff B, Peichl P, Palfi G, Schnitzel W, Mlynar E, et al.Mode of action of SDZ NIM811, a nonimmunosuppressive cyclosporin A analog with activity against humanimmunodeficiency virus type 1 (HIV-1): interference with early and late events inHIV-1 replication.J Virol.1995; 69 (2): 814-824.] suppress the activity of CypA, all can disturb duplicating of HIV-1 virus.
Yet up to the present, the someone reports the CypA inhibitor with anti HIV-1 virus as yet.
Summary of the invention
The purpose of this invention is to provide the application of a kind of chemical compound in the preparation anti-AIDS drug.
The invention provides the application of a kind of chemical compound in the preparation anti-AIDS drug, the structure of this chemical compound is:
Wherein, R
1Be 4-fluoro-3-aminomethyl phenyl, 4-fluoro-phenyl, 1H-indole-5-base, benzofuran-5-base, phenyl, 4-amino-3-aminomethyl phenyl or 4-bromo-3-aminomethyl phenyl; R
2Be the 2-phenyl, 2-bromophenyl, 2-aminomethyl phenyl, 2-aminophenyl or 2-fluorophenyl.The present invention comprises that also above-claimed cpd is carried out routine substitutes resulting chemical compound, is referred to as ASD5.
Among the present invention, R
1Can be 4-bromo-3-aminomethyl phenyl.
Among the present invention, R
2Can be the 2-fluorophenyl.
In one embodiment of the present of invention, R
1Be 4-bromo-3-aminomethyl phenyl, R
2Be the 2-fluorophenyl, described chemical compound is N-(4-bromo-3-aminomethyl phenyl)-N-{2-[4-(2-fluorobenzoyl-1-piperazinyl) ethyl] oxalamide (be N-(4-bromo-3-methylphenyl)-N '-2-[4-(2-fluorobenzoyl-1-piperazinyl) ethyl] ethanediamide) structural formula is:
May disturb duplicating of HIV-1 virus in view of suppressing the active material of CypA, the avtive spot that the present invention is directed to CypA has designed some micromolecular inhibitors.Owing to be medicine, and cell target spot mutation rate with respect to viral target spot is relatively slow at the design of cell target spot, therefore be difficult for forming drug resistance, be fit to the demand of the lifelong medication of AIDS patient.
At first, the present invention has carried out virtual screening to the CypA micromolecular inhibitor.
Cyclophilin A (CypA, PPIA) gene is logged in the human genome data base, and its typing number is NM_021130.In PDB protein structure data base, retrieved the proteic X-ray diffraction crystal of human CypA structure (PDB code: 1CWA).This structure is the compound crystal structure of CypA and its natural inhibitor cyclosporin A (CsA).From this structure, determined the avtive spot of CypA, and determined in the avtive spot, can be by some key amino acids site that CsA suppressed.According to these structural informations, the present invention is directed to the CypA avtive spot, some micromolecule data bases are screened.The micromolecule data base who is used to screen mainly comprises SPECS and CNPD, has screened ASD5 of the present invention at last.Whole computational process is to carry out on Chinese Academy of Sciences's Shanghai medicine institute 64CPU-SGI ORIGN3800 computer and super calculation center, Shanghai 392CPU-martial prowess I supercomputer.
Secondly, the present invention utilizes the BIAcore molecule to make instrument checking virtual screening result mutually
The BIAcore molecule is based on surface plasma resonance technology as instrument mutually and realizes following the tracks of interaction between biomolecule, need not any label, has therefore guaranteed the verity of experimental result to greatest extent.During experiment, biological molecules of interest (CypA albumen) is fixed on the sensing chip surface, then micromolecular compound is dissolved in solvent and flows through chip surface.Monitor can real-time tracking detects combine, the dissociate variation of whole process of molecule and chip surface biological molecules of interest in the solution.By the binding data of BIAcore, we have determined that finally 12 can bonded micromolecular compound take place with CypA, and have calculated these micromolecular compounds and the bonded balance of CypA-dissociation constant KD.
Once more, the present invention utilizes enzyme work to experimental results show that the ability that micromolecular compound is lived and suppressed the CypA enzyme, thereby seeks out the inhibitor of CypA.
It is a lot of to measure the active method of CyP, but the most frequently used with alpha-chymotrypsin activation measurement (α-chymotrypsin-coupled enzymic assay).Its principle is the oligopeptide substrate that contains proline, be in balance as N-succinyl-Ala-Ala-Pro-Phe paranitroanilinum (N-Succinyl-Ala-Ala-Pro-Phe p-nitroanilide) its cis, transconfiguration in solution, this substrate generation cis-trans isomerism effect of CyP energy catalysis, promptly the catalysis proline is become trans by cis; When it was in transconfiguration, C end p-nitroanilide was discharged pigment group paranitroanilinum by the alpha-chymotrypsin cracking, can learn the PPIase activity of CyP in the variation of 390nm METHOD FOR CONTINUOUS DETERMINATION light absorption value.
We react in contrast with the reaction that does not add micromolecular inhibitor, measure the suppression ratio that each micromolecule part is lived and reacted enzyme under variable concentrations, thereby calculate the IC of each micromolecule part
50Value.
At last, the present invention has also measured the influence of CypA micromolecular inhibitor to the HIV-1 virus replication
Chemical compound anti-HIV-1 virus increment test: briefly, utilize the double antibodies sandwich method to measure the amount that p24 albumen produces in each hole exactly.Absorbance value with the blank hole is reference, calculates each chemical compound and suppresses the IC that HIV-1 virus p24 albumen produces
50Value.Result: N-(4-bromo-3-aminomethyl phenyl)-N-{2-[4-(2-fluorobenzoyl-1-piperazinyl) ethyl] oxalamide suppresses the IC that HIV-1 virus p24 albumen produces
50Value (ug/ml) is 61.08 ± 4.00.As seen, N-(4-bromo-3-aminomethyl phenyl)-N-{2-[4-(2-fluorobenzoyl-1-piperazinyl) ethyl] oxalamide has the ability that suppresses the HIV-1 virus replication, and can be used as new anti-AIDS drug and develop.
Micromolecular compound of the present invention can adopt the preparation method preparation of various routines.For example, adopt the method for artificial chemosynthesis.
Utilize micromolecular compound of the present invention,, can filter out with ASD5 interactional material takes place, as receptor, inhibitor or antagonist etc. by various conventional screening techniques.
The present invention and inhibitor, antagonist etc. when using (administration) in treatment, can provide different effects.Usually, can these materials are formulated in nontoxic, the inert and pharmaceutically acceptable aqueous carrier medium, wherein pH is about 5-8 usually, and preferably pH is about 6-8, although pH value can be with being changed to some extent by preparation Substance Properties and disease to be treated.The pharmaceutical composition for preparing can carry out administration by conventional route, comprising (but being not limited to): intramuscular, intraperitoneal, subcutaneous, Intradermal or topical.
With people ASD5 of the present invention is example, can be with itself and suitable pharmaceutically acceptable carrier coupling.This class pharmaceutical composition contains chemical compound and the pharmaceutically acceptable carrier or the excipient for the treatment of effective dose.This class carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should be complementary with administering mode.People ASD5 of the present invention can be made into the injection form, for example is prepared by conventional method with normal saline or the aqueous solution that contains glucose and other adjuvant.Pharmaceutical composition such as tablet and capsule can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule should be made under aseptic condition.The dosage of active component is the treatment effective dose, for example every day about 1 microgram/kg body weight-Yue 5 mg/kg body weight.In addition, ASD5 of the present invention also can use with the other treatment agent.
In the application of people ASD5 of the present invention in the preparation anti-AIDS drug, can be injection or tablet.
When people ASD5 polypeptide of the present invention is used as medicine, this polypeptide of treatment effective dose can be applied to mammal, wherein should treat effective dose usually at least about 10 micrograms/kg body weight, and in most of the cases be no more than about 8 mg/kg body weight, preferably this dosage is about 10 micrograms/kg body weight-Yue 1 mg/kg body weight.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
Acquired immune deficiency syndrome (AIDS) (AIDS) is a kind of by HIV (human immunodeficiency virus) (Human Immunodeficiency Virus), be HIV (human immunodeficiency virus) (humanimmunodeficiencyvirus, abbreviation HIV) destroys immune function of human body behind the intrusion human body, make human body that the multiple infection that can not cure and tumor take place, cause a kind of serious infectious disease of infected person's death at last.The acquired immune deficiency syndrome (AIDS) that is called as " contemporary pestilence " and " super cancer " has caused the great attention of The World Health Organization (WHO) and national governments, the input that no matter is personnel and funds is all put in the first place, China has listed it in the Class B Notifiable disease, and is one of border monitoring of hygiene infectious disease.Yet, up to the present, still do not have and can cure this sick active drug.Micromolecular compound ASD5 of the present invention has the ability that suppresses the HIV-1 virus replication, and is the medicine at the design of cell target spot, is difficult for forming drug resistance, is fit to the demand of the lifelong medication of AIDS patient.Therefore, ASD5 of the present invention can be used as new anti-AIDS drug and develops, for the treatment and treatment of AIDS a kind of new approach and means are provided.
The specific embodiment
The virtual screening of embodiment 1 CypA micromolecular inhibitor
Cyclophilin A (CypA, PPIA) gene is logged in the human genome data base, and its typing number is NM_021130.In PDB protein structure data base, we have retrieved the proteic X-ray diffraction crystal of human CypA structure (PDB code: 1CWA).This structure is the compound crystal structure of CypA and its natural inhibitor cyclosporin A (CsA).From this structure, we have determined the avtive spot of CypA, and have determined in the avtive spot, can be by some key amino acids site that CsA suppressed.According to these structural informations, we and Chinese Academy of Sciences's Shanghai medicine are cooperated, and at the CypA avtive spot, some micromolecule data bases are screened.The micromolecule data base who is used to screen mainly comprises SPECS and CNPD.Screened ASD5 of the present invention at last.Whole computational process is to carry out on the Chinese Academy of Sciences's Shanghai medicine 64CPU-SGIORIGN3800 of institute computer and super calculation center, Shanghai 392CPU-martial prowess I supercomputer.
Embodiment 2 utilizes the BIAcore molecule to make instrument checking virtual screening result mutually
The BIAcore molecule is based on surface plasma resonance technology as instrument mutually and realizes following the tracks of interaction between biomolecule, need not any label, has therefore guaranteed the verity of experimental result to greatest extent.During experiment, biological molecules of interest (CypA albumen) is fixed on the sensing chip surface, then micromolecular compound is dissolved in solvent and flows through chip surface.Monitor can real-time tracking detects combine, the dissociate variation of whole process of molecule and chip surface biological molecules of interest in the solution.By the binding data of BIAcore, we have determined that finally 12 can bonded micromolecular compound take place with CypA, and have calculated these micromolecular compounds and the bonded balance of CypA-dissociation constant KD.The result shows, ASD5 of the present invention can with the CypA protein-interacting.
Embodiment 3 chemical compound anti-HIV-1s virus increment test
MT-2 cell kind in 96 orifice plates, every hole 10
4Individual.Culture medium is the RPMI1640 culture medium that contains 10% hyclone.HIV-1 virus is come infection cell with 100 50% tissue infection equivalents, adds the chemical compound overnight incubation (is blank with the hole that does not add chemical compound) of variable concentrations gradient simultaneously.Next day, change the fresh culture that does not contain micromolecular compound.The 4th day, get 100uL culture fluid supernatant, after handling, the Triton-X100 that adds 5% volume obtains employing virus cracking liquid, measure p24 protein content (p24 is the coat protein of HIV-1, can be used as the index of measurement virion quantity) with the ELISA method then.Briefly, utilize the double antibodies sandwich method to measure the amount that p24 albumen produces in each hole exactly.To resist HIV immunoglobulin wrapper sheet to spend the night (pH9.6 carbonic acid buffer, 4 ℃), add the PBS sealing that contains 4% defatted milk powder then; Hatched usefulness pre-cooling PBS flushing several times 1 hour in 37 ℃ after adding the 100uL employing virus cracking liquid; The anti-p24 monoclonal antibody that adds horseradish peroxidase-labeled is with the TMB a quarter that develops the color; The sulfuric acid solution cessation reaction that adds 1N then, the absorbance value when on microplate reader, reading 450nm.Absorbance value with the blank hole is reference, calculates each chemical compound and suppresses the IC that HIV-1 virus p24 albumen produces
50Value.
Result: N-(4-bromo-3-aminomethyl phenyl)-N-{2-[4-(2-fluorobenzoyl-1-piperazinyl) ethyl] oxalamide (CAS No 496941-01-6, Specs AO-081/15570018) suppresses the IC that HIV-1 virus p24 albumen produces
50Be worth following (ug/ml): 61.08 ± 4.00.
Claims (4)
1. the application of chemical compound in the preparation anti-AIDS drug is characterized in that this structural formula of compound is:
Wherein, R
1Be 4-fluoro-3-aminomethyl phenyl, 4-fluoro-phenyl, 1H-indole-5-base, benzofuran-5-base, phenyl, 4-amino-3-aminomethyl phenyl or 4-bromo-3-aminomethyl phenyl; R
2Be the 2-phenyl, 2-bromophenyl, 2-aminomethyl phenyl, 2-aminophenyl or 2-fluorophenyl.
2. application as claimed in claim 1 is characterized in that R
1Be 4-bromo-3-aminomethyl phenyl.
3. application as claimed in claim 1 is characterized in that R
2Be the 2-fluorophenyl.
4. application as claimed in claim 1 is characterized in that, this anti-AIDS drug is injection or tablet.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010127558A1 (en) * | 2009-05-05 | 2010-11-11 | 中国科学院上海药物研究所 | Substituted benzoyl urea compounds, preparation methods and uses thereof |
| WO2017173048A1 (en) * | 2016-03-31 | 2017-10-05 | Merck Patent Gmbh | Compounds for the inhibition of cyclophilins and uses thereof |
| WO2017173049A1 (en) * | 2016-03-31 | 2017-10-05 | Merck Patent Gmbh | Compounds for the inhibition of cyclophilins and uses thereof |
-
2006
- 2006-07-20 CN CNB2006100291731A patent/CN100502869C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010127558A1 (en) * | 2009-05-05 | 2010-11-11 | 中国科学院上海药物研究所 | Substituted benzoyl urea compounds, preparation methods and uses thereof |
| CN101880246B (en) * | 2009-05-05 | 2012-10-03 | 中国科学院上海药物研究所 | Substituted benzoyl urea compound and preparation method and application thereof |
| WO2017173048A1 (en) * | 2016-03-31 | 2017-10-05 | Merck Patent Gmbh | Compounds for the inhibition of cyclophilins and uses thereof |
| WO2017173049A1 (en) * | 2016-03-31 | 2017-10-05 | Merck Patent Gmbh | Compounds for the inhibition of cyclophilins and uses thereof |
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| CN100502869C (en) | 2009-06-24 |
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