CN102727478A - Application of retinoic acid and its derivatives in preparation of drugs preventing and treating renal fibrosis - Google Patents
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- 0 CCC(C)(C)C(C=CC(c1ccc(C(C)C)cc1)=C*=CC(Br=C)=CC)=C Chemical compound CCC(C)(C)C(C=CC(c1ccc(C(C)C)cc1)=C*=CC(Br=C)=CC)=C 0.000 description 3
- TYOQXSCZVULWEE-NTVGQSGVSA-N CC/C(/C=C/c1ccc(C(C)(C)CCC2(C)C)c2c1)=C\C(C)C/C=C/C(O)=O Chemical compound CC/C(/C=C/c1ccc(C(C)(C)CCC2(C)C)c2c1)=C\C(C)C/C=C/C(O)=O TYOQXSCZVULWEE-NTVGQSGVSA-N 0.000 description 1
- VJTWLGGOAXGLPZ-JEBUDGLKSA-N CC1(C)c2ccc(/C=C/C(/c3ccc(C)cc3)=C/C=C/C(/Br)=C/C(O)=O)cc2C(C)(C)CC1 Chemical compound CC1(C)c2ccc(/C=C/C(/c3ccc(C)cc3)=C/C=C/C(/Br)=C/C(O)=O)cc2C(C)(C)CC1 VJTWLGGOAXGLPZ-JEBUDGLKSA-N 0.000 description 1
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Abstract
The invention discloses application of retinoic acid and its derivatives in preparation of drugs preventing and treating renal fibrosis. Relevant study of the invention finds that transcription factor AP-1 is a key regulation factor for excessive activation of fibroblasts, while specific inhibition of AP-1 activity by retinoic acid and its derivatives can effectively reduce the fibroblast activation degree and relieve the attack degree and symptoms of renal fibrosis. In the invention, through specific inhibition of the AP-1 activity by retinoic acid and its derivatives, the fibroblast activation degree can be effectively reduced, and the attack degree and symptoms of renal fibrosis can be relieved. Thus, retinoic acid and its derivatives are a drug candidate molecule used for preventing and treating renal fibrosis. Meanwhile, the small molecular drugs adopted in the invention are characterized by easy acquisition, low price, stable property, as well as convenient storage and transport.
Description
Technical field
The invention belongs to the biological medicine technology field, be specifically related to tretinoin and derivative compound thereof and prevent and treat the application in the disease medicament that renal fibrosis is main pathological characters in preparation.
Background technology
Renal fibrosis is that renal fibrosis is a kind of pathophysiological change, be kidney function by health to the damage, arrive damage again, until the progressive process of afunction.Kidney is owing to receive wound, infection, inflammation, blood circulatory disorder, and multiple paathogenic factor such as immunoreation stimulates, and its intrinsic cell is impaired; Develop into the later stage occur a large amount of collagen depositions with gather; Cause excess of the kidney matter to harden gradually, form cicatrix, completely lose organ function until kidney.Intrinsic cell fibrosis, the hardened process process of renal fibrosis just in the kidney.Renal fibrosis is that abnormal deposition with extracellular matrix (ECM) is a characteristic.It is fibroblastic overactivity that the basic pathology of renal fibrosis is learned reason, is suppressed to fibrocellular overactivity, can effectively suppress the development of renal fibrosis.Discover through the inventor; Transcription factor AP-1 is the overactive crucial regulation and control factor of fibroblast in the renal fibrosis process; And can effectively be lowered into fibrocellular activation degree through the activity of retionic acid and derivant specificity inhibition AP-1 thereof, alleviate the occurring degree and the symptom of renal fibrosis.Therefore, retionic acid and derivant thereof are a kind of drug candidate molecules that is used to prevent and treat renal fibrosis with development potentiality.
Summary of the invention
The object of the present invention is to provide a kind of crucial transcription factor AP-1 that can pass through to suppress; Thereby can be lowered into the fibrocyte activation degree, the micromolecular compound that delays the renal fibrosis incidence and development is tretinoin and the application of derivant in preparation control renal fibrosis medicine thereof.
Tretinoin and the application of derivant in preparation control renal fibrosis medicine thereof with following structural formula (I) of the present invention,
Wherein, R1 is COOH or COH or CH2OH; R2, R4, R5, R6, R8, R9 respectively do for oneself H or C1-C6 alkyl; R3, R7 respectively do for oneself H or C1-C6 alkyl or aromatic radical or halogen or nitro or alkoxyl.Structure includes but not limited to following chemical compound shown in the structure formula I at this moment:
chemical compound 3:9-(2; 6; The 6-trimethyl cyclohexene)-2; 4,6,8-alltrans tetraene in ninth of the ten Heavenly Stems aldehyde
chemical compound 7:8-ethyl-9-(2; 6, the 6-trimethyl cyclohexene) nona tetraenoic acid
chemical compound 37:3-nitro-7-p-methylphenyl-9-(2; 6, the 6-trimethyl cyclohexene) nona tetraenoic acid
chemical compound 41:3; 7-two p-methylphenyls-9-(2; 6, the 6-trimethyl cyclohexene) nona tetraenoic acid
Said R1 is preferably COOH; Said aromatic radical is preferably and does not replace or the substituted phenyl of alkyl.
Said alkyl-substituted phenyl is preferably single or polysubstituted aminomethyl phenyl and comprises p-methylphenyl or 2-aminomethyl phenyl or 2,4-3,5-dimethylphenyl or 2,6-3,5-dimethylphenyl or 2,4,6-trimethylphenyl etc.
In the structure formula I, can preferably work as R1 is COOH; R2, R4, R5, R6, R8, R9 is H; R3 is H or C1-C6 alkyl, and R7 is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
In the structure formula I, also can preferably work as R1-COOH; R2, R4, R5, R6, R7, R8, R9 is H; R3 is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
In the structure formula I, also can preferably work as R1 is COOH; R2, R4, R5, R6, R8, R9 is H; R3 is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl, and R7 is not for replacing or alkyl-substituted phenyl.
Said alkyl-substituted phenyl is preferably single or polysubstituted aminomethyl phenyl and comprises p-methylphenyl or 2-aminomethyl phenyl or 2,4-3,5-dimethylphenyl or 2, and 6-3,5-dimethylphenyl or 2,4,6-trimethylphenyl etc., most preferred alkyl-substituted phenyl is a p-methylphenyl.
The application of retinoic acid derivatives in preparation control renal fibrosis medicine with following structural formula (II) of the present invention,
Wherein, R1 ' is COOH or COH or CH2OH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' respectively do for oneself H or C1-C6 alkyl; R3 ', R7 ' respectively do for oneself H or C1-C6 alkyl or aromatic radical or halogen or nitro or alkoxyl, structure includes but not limited to following chemical compound shown in structural formula this moment (II):
chemical compound 4: (2E, 4E, 6E, 8E)-9-(5; 5,8,8-tetramethyl-5; 6,7,8-tetralyl-2-yl)-2; 4,6,8-tetraene aldehyde C-9
chemical compound 12: (2E, 4E, 6E, 8E)-9-methyl-6-ethyl-9-(5; 5,8,8-tetramethyl-5; 6,7,8-tetralyl-2-yl)-2; 4,6,8-tetraene n-nonanoic acid
Said R1 ' is preferably COOH; Said aromatic radical is preferably and does not replace or the substituted phenyl of alkyl;
Said alkyl-substituted phenyl is preferably single or polysubstituted aminomethyl phenyl and comprises p-methylphenyl or 2-aminomethyl phenyl or 2,4-3,5-dimethylphenyl or 2,6-3,5-dimethylphenyl or 2,4,6-trimethylphenyl etc.
In the structural formula (II), preferred, working as R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' is H; R3 ' is H or C1-C6 alkyl, and R7 ' is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
In the structural formula (II), also can preferably work as R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R7 ', R8 ', R9 ' is H; R3 ' is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
In the structural formula (II), also preferably R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' is H; R3 ' is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl, and R7 ' is not for replacing or alkyl-substituted phenyl.
Said alkyl-substituted phenyl is preferably single or polysubstituted aminomethyl phenyl and comprises p-methylphenyl or 2-aminomethyl phenyl or 2,4-3,5-dimethylphenyl or 2, and 6-3,5-dimethylphenyl or 2,4,6-trimethylphenyl etc., most preferred alkyl-substituted phenyl is a p-methylphenyl.
Tretinoin of the present invention and derivant thereof can be processed pharmaceutically acceptable various dosage form according to the method for conventional medicine preparation, adopt different administering modes according to pharmaceutical dosage form then.
Compound structure list of references of the present invention (Nature, 372:107-110,1994.) report can be become service organization to provide by the compounds of specialty, the chemical compound that the present invention uses is from Shanghai Yaoming Kangde New Medicine Development Co., Ltd.
Tretinoin of the present invention and derivative compound thereof can oral, vein, nasal cavity, rectum or other any mode administrations that can carry the active substance of effective dose.Proper dosage is those dosage that can obtain needed final quantity.Also possibly need different dosages and prevent and treat different disease.
Research worker with routine techniques can be confirmed the most effectively dosage and time consideration administering mode of the reagent that this invention provides, drug metabolism, and some other pharmacokinetic parameter drug distribution for example, clearance rate etc.
Active reagent can be through a pharmaceutical carrier or diluent administration.This reagent of being provided of invention can also for example chemotherapy or immune activation medicine be perhaps prevented and treated medication combined administration with other reagent.The pharmaceutical carrier that this invention is suitable for or the instance of diluent comprise any physiological buffer that is dissolved with the water solublity organic carrier, and for example cyclodextrin phosphate buffer and pH7.0's to 7.4 contains suitable other buffer of water solublity organic carrier.Suitable water solublity organic carrier includes, but are not limited to cyclodextrin, Semen Maydis oil, DMSO, capsule etc.
The present invention is through carrying out illustration to the renal fibrosis model in the body.The animal here includes, but are not limited to: mice, rat, performing animal includes, but are not limited to cat, Canis familiaris L., and some other animal for example but be not limited to cattle, sheep, pig, horse, primate for example but be not limited to monkey and people.Detect in the body of kidney of rats fibrosis model by the active model that detects of the drug disposition of extensive recognition and acceptance, also can be other biology people for example simultaneously, but being not limited only to the people provides reference.
Tretinoin of the present invention and derivative compound thereof are in the application of control renal fibrosis; A kind of use of single chemical compound tretinoin and derivative compound thereof can prevent and treat renal fibrosis; So obvious, various forms of being mixed of above-claimed cpd also can reach certain therapeutic effect.
The invention provides the application in preparation prevention control renal fibrosis disease medicament of a kind of tretinoin and derivative compound thereof, through give tretinoin and derivative compound thereof with and preparation suppress and block the outbreak of renal fibrosis.Simultaneously, small-molecule drug used in the present invention is easy to obtain, and is cheap, and stable in properties is convenient to storage and transport.
The specific embodiment
Following Example should not regarded as the restriction to connotation of the present invention in order to explain the present invention but these those skilled in the technology concerned should be appreciated that it.
[zoopery example]
1, tretinoin and derivant thereof are to the influence of one-sided ureter ligation kidney of rats interstitial fibrosis
1.1 material
It is subsequent use respectively above-mentioned listed chemical compound to be made into the 2.0mg/ml oral administration solution with Semen Maydis oil dissolving.
Hydroxyproline (HYP) test kit; Fibronectin (FN) test kit.
Laboratory animal regular grade Wistar rat, male, body weight 150-200g, SD rat.
1.2 test method and result
With rat, the treatment group that is divided into sham operated rats group, model control group at random and treats with the above-mentioned compound solution for preparing respectively, 10 every group.1 week of animal feeding, each rat with 10% chloral hydrate 3.0ml/kg intraperitoneal injection of anesthesia after, the rat RAR is fixed on the operating-table; With iodine tincture, 75% alcohol disinfecting field of operation, row left side abdomen otch successively cuts skin, muscle and each layer of stomach wall after the cropping; Expose and also to separate the left side ureter, sham operated rats is only cut abdominal cavity and free left side ureter, but not ligation with cut off; Other respectively organize rat with 4-0 silk thread ligation twice, and last one ligation point is positioned at right inferior pole of kidney level, between twice ligation point, cuts off ureter then; Layer-by-layer suture; Postoperative was put to death each treated animal after the chloral hydrate anesthesia in 10 days 10%, got blood, pressed Fibronectin and measured explanation mensuration Fibronectin.Normal saline is retained left kidney after the lavation repeatedly, and nephridial tissue is fixed through 4% paraformaldehyde buffer.Cut an amount of nephridial tissue, press the explanation of hydroxyproline kit measurement and measure hydroxyproline.
Routine pathology is learned inspection:
(1), macroscopy: sham operated rats kidney color is scarlet, smooth surface, peplos gloss, no adhesion.Other respectively organize the increase of kidney volume, and color is pale, and the surface is graininess, similar human body branny kidney, the adhesion of few regions kidney peplos.
(2), light microscopy checking: sham operated rats nephron clear in structure, glomerular capsule do not have expansion or dwindle, and renal cells does not have obvious degeneration and necrosis, do not have come off epithelial cell or cast, no vasodilation or cell infiltration in the matter in the official jargon.The large stretch of renal tubular necrosis of model control group, the hyperplasia of kidney interstitial fibers, tubular ectasia, in large stretch of pale brown color refractive power material or the downright bad epithelial cell that comes off are arranged, the glomerule decreased number, part glomerule fibrosis and with the adhesion of Bowman wall, blister cavities disappears.Administration respectively organizes pathological changes and model group is similar, but all has morphology in various degree to improve, and with model control group notable difference is arranged relatively.
Each group FN, HYP are carried out the T check.The result sees table 1.
Medication therapy groups obviously reduce FN, HYP level (with model control group relatively, P 0.01).
Table 1: tretinoin and derivant thereof are to the influence of one-sided ureter ligation kidney of rats interstitial fibrosis
| Group | Example number (only) | Hydroxyproline (μ g/g) | Fibronectin (mg/L) |
| Sham operated rats | 10 | 321±56 | 5.2±1.5 |
| Model control group | 10 | 744±151 | 25.2±5.2 |
| Chemical compound 1 treatment group | 10 | 556±98 | 16.6±3.5 |
| Chemical compound 2 treatment groups | 10 | 517±93 | 16.2±6.8 |
| Chemical compound 3 treatment groups | 10 | 548±89 | 14.5±5.5 |
| Chemical compound 4 treatment groups | 10 | 507±94 | 15.7±6.3 |
| Chemical compound 5 treatment groups | 10 | 506±75 | 16.6±6.1 |
| Chemical compound 6 treatment groups | 10 | 524±85 | 14.4±4.7 |
| Chemical compound 7 treatment groups | 10 | 511±93 | 15.6±3.1 |
| Chemical compound 8 treatment groups | 10 | 554±79 | 14.3±3.3 |
| Chemical compound 9 treatment groups | 10 | 516±73 | 14.9±4.3 |
| Chemical compound 10 treatment groups | 10 | 522±76 | 14.4±5.7 |
| Chemical compound 11 treatment groups | 10 | 517±95 | 15.1±5.6 |
| Chemical compound 12 treatment groups | 10 | 554±99 | 14.8±3.9 |
| Chemical compound 13 treatment groups | 10 | 521±82 | 14.7±3.3 |
| Chemical compound 14 treatment groups | 10 | 511±99 | 15.9±6.3 |
| Chemical compound 15 treatment groups | 10 | 527±88 | 15.7±4.4 |
| Chemical compound 16 treatment groups | 10 | 546±91 | 16.9±5.8 |
| Chemical compound 17 treatment groups | 10 | 559±95 | 15.1±6.3 |
| Chemical compound 18 treatment groups | 10 | 552±82 | 14.9±5.7 |
| Chemical compound 19 treatment groups | 10 | 504±80 | 15.6±3.6 |
| Chemical compound 20 treatment groups | 10 | 533±90 | 16.2±6.4 |
| Chemical compound 21 treatment groups | 10 | 532±88 | 14.8±5.3 |
| Chemical compound 22 treatment groups | 10 | 557±81 | 16.1±2.9 |
| Chemical compound 23 treatment groups | 10 | 501±90 | 14.1±6.6 |
| Chemical compound 24 treatment groups | 10 | 501±82 | 15.6±3.7 |
| Chemical compound 25 treatment groups | 10 | 560±99 | 15.7±3.4 |
| Chemical compound 26 treatment groups | 10 | 536±76 | 15.7±5.1 |
| Chemical compound 27 treatment groups | 10 | 518±88 | 14.5±3.3 |
| Chemical compound 28 treatment groups | 10 | 535±76 | 16.4±4.6 |
| Chemical compound 29 treatment groups | 10 | 520±87 | 14.4±3.5 |
| Chemical compound 30 treatment groups | 10 | 546±80 | 14.7±4.8 |
| Chemical compound 31 treatment groups | 10 | 527±94 | 14.4±5.2 |
| Chemical compound 32 treatment groups | 10 | 543±78 | 15.7±4.7 |
| Chemical compound 33 treatment groups | 10 | 551±96 | 16.2±5.2 |
| Chemical compound 34 treatment groups | 10 | 547±76 | 15.2±4.3 |
| Chemical compound 35 treatment groups | 10 | 528±78 | 15.1±4.4 |
| Chemical compound 36 treatment groups | 10 | 511±86 | 15.9±3.3 |
| Chemical compound 37 treatment groups | 10 | 530±82 | 15.8±5.9 |
| Chemical compound 38 treatment groups | 10 | 516±96 | 14.1±3.5 |
| Chemical compound 39 treatment groups | 10 | 551±85 | 14.7±3.4 |
| Chemical compound 40 treatment groups | 10 | 536±83 | 15.3±3.2 |
| Chemical compound 41 treatment groups | 10 | 527±82 | 15.6±2.9 |
| Chemical compound 42 treatment groups | 10 | 519±76 | 16.6±6.9 |
| Chemical compound 43 treatment groups | 10 | 540±75 | 15.9±3.7 |
| Chemical compound 44 treatment groups | 10 | 518±78 | 14.5±3.6 |
| Chemical compound 45 treatment groups | 10 | 545±93 | 15.2±53 |
| Chemical compound 46 treatment groups | 10 | 547±72 | 15.3±4.4 |
Claims (10)
1. the tretinoin and the application of derivant in preparation control renal fibrosis medicine thereof that have following structural formula (I),
Wherein, R1 is COOH or COH or CH2OH; R2, R4, R5, R6, R8, R9 respectively do for oneself H or C1-C6 alkyl; R3, R7 respectively do for oneself H or C1-C6 alkyl or aromatic radical or halogen or nitro or alkoxyl.
2. application as claimed in claim 1 is characterized in that: R1 is COOH; R2, R4, R5, R6, R8, R9 is H; R3 is H or C1-C6 alkyl, and R7 is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
3. application as claimed in claim 1 is characterized in that: R1 is COOH; R2, R4, R5, R6, R7, R8, R9 is H; R3 is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
4. application as claimed in claim 1 is characterized in that: R1 is COOH; R2, R4, R5, R6, R8, R9 is H; R3 is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl, and R7 is not for replacing or alkyl-substituted phenyl.
5. application as claimed in claim 4 is characterized in that: R7 is a p-methylphenyl.
6. the application of retinoic acid derivatives in preparation control renal fibrosis medicine that has following structural formula (II),
Wherein, R1 ' is COOH or COH or CH2OH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' respectively do for oneself H or C1-C6 alkyl; R3 ', R7 ' respectively do for oneself H or C1-C6 alkyl or aromatic radical or halogen or nitro or alkoxyl.
7. application as claimed in claim 6 is characterized in that: R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' is H; R3 ' is H or C1-C6 alkyl, and R7 ' is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
8. application as claimed in claim 6 is characterized in that: R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R7 ', R8 ', R9 ' is H; R3 ' is unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl.
9. application as claimed in claim 6 is characterized in that: R1 ' is COOH; R2 ', R4 ', R5 ', R6 ', R8 ', R9 ' is H; R3 ' is H or C1-C6 alkyl or unsubstituted phenyl or alkyl-substituted phenyl or halogen or nitro or alkoxyl, and R7 ' is not for replacing or alkyl-substituted phenyl.
10. like each described application among the claim 1-9, it is characterized in that: said tretinoin and derivant thereof are processed pharmaceutically acceptable dosage form according to the method for conventional medicine preparation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023241716A1 (en) * | 2022-06-16 | 2023-12-21 | 中国科学院动物研究所 | Method for inducing in-situ regeneration of mammal and use thereof |
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| CN101102795A (en) * | 2004-12-22 | 2008-01-09 | 北海道公立大学法人札幌医科大学 | Drug carrier and drug carrier kit for inhibiting fibrosis |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023241716A1 (en) * | 2022-06-16 | 2023-12-21 | 中国科学院动物研究所 | Method for inducing in-situ regeneration of mammal and use thereof |
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Application publication date: 20121017 |