CN103356659A - Application of Chukrasone A in preparing medicines for treating or preventing renal fibrosis - Google Patents
Application of Chukrasone A in preparing medicines for treating or preventing renal fibrosis Download PDFInfo
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- CN103356659A CN103356659A CN 201310279831 CN201310279831A CN103356659A CN 103356659 A CN103356659 A CN 103356659A CN 201310279831 CN201310279831 CN 201310279831 CN 201310279831 A CN201310279831 A CN 201310279831A CN 103356659 A CN103356659 A CN 103356659A
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- Prior art keywords
- chukrasone
- renal fibrosis
- treating
- application
- preparing medicines
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- 201000002793 renal fibrosis Diseases 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title claims abstract description 12
- HZUBWSRMDOJYPS-WPCVKUBSSA-N chukrasone A Natural products C=1([C@@H]2OC(=O)C[C@H]3[C@@]4(O)[C@H](O)C(=O)[C@@]5(O)[C@@H](OC(=O)C(C)C)C(C)(C)[C@@H]([C@]5([C@H]4[C@H](OC(C)=O)C[C@]32C)C)CC(=O)OC)C=COC=1 HZUBWSRMDOJYPS-WPCVKUBSSA-N 0.000 title abstract description 26
- 229940079593 drug Drugs 0.000 title abstract 4
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 6
- 229930187319 chukrasone Natural products 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 210000003734 kidney Anatomy 0.000 description 14
- 241000700159 Rattus Species 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 9
- 102000016359 Fibronectins Human genes 0.000 description 7
- 108010067306 Fibronectins Proteins 0.000 description 7
- 206010016654 Fibrosis Diseases 0.000 description 7
- 230000004761 fibrosis Effects 0.000 description 7
- 238000003304 gavage Methods 0.000 description 7
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 5
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 5
- 229960002591 hydroxyproline Drugs 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 5
- 241001156380 Chukrasia tabularis Species 0.000 description 3
- 108010087141 Kv1.2 Potassium Channel Proteins 0.000 description 3
- 102000006628 Kv1.2 Potassium Channel Human genes 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003450 potassium channel blocker Substances 0.000 description 3
- 210000000626 ureter Anatomy 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 2
- 101000693993 Homo sapiens Sodium channel protein type 4 subunit alpha Proteins 0.000 description 2
- 208000007599 Hyperkalemic periodic paralysis Diseases 0.000 description 2
- 102100027195 Sodium channel protein type 4 subunit alpha Human genes 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 229960004530 benazepril Drugs 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 102000010970 Connexin Human genes 0.000 description 1
- 108050001175 Connexin Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000031816 Pathologic Dilatation Diseases 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010038540 Renal tubular necrosis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000002665 bowman capsule Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000885 nephron Anatomy 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000002550 vasoactive agent Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an application of Chukrasone A in preparing medicines for treating or preventing renal fibrosis, and belongs to the technical field of novel use of medicines. The use of the Chukrasone A in preparing medicines for treating renal fibrosis provided by the invention is disclosed for the first time. As the framework type belongs to a brand-new framework type, and the inhibitory activity of the Chukrasone A to renal fibrosis is unimaginably strong, the probability of giving any enlightenment by other compounds does not exist. The Chukrasone A has remarkable substantial characteristics and meanwhile has a remarkable progress for preventing and treating renal fibrosis.
Description
Technical field
The present invention relates to a kind of new medicine use, relate to particularly the application of Chukrasone A in the medicine of preparation treatment or preventing renal fibrosis.
Background technology
Renal fibrosis (comprising kidney region fibrosis and glomerular sclerosis) is the main pathological basis of the kidney damage final stage that causes of a variety of causes, the renal fibrosis mechanism is comparatively complicated, relevant with many factors, wherein main and the celliferous propagation of extracellular matrix cell and activation, vaso-active substance, cytokine and extracellular matrix are changed unbalance relevant, so kidney region fibrosis almost is the common pathway that former or secondary kidney disease proceed to end stage renal failure.
The Compound C hukrasone A that the present invention relates to is one and delivered (Liu in 2012, H. B. et al., 2012. Chukrasones A and B:Potential Kv1.2 Potassium Channel Blockers with New Skeletons from Chukrasia tabularis. Organic Letters 14 (17), 4438 – 4441.) New skeleton compound, this chemical compound has brand-new framework types, present purposes only relates to potassium-channel and suppresses active (Liu, H. B. et al., 2012. Chukrasones A and B:Potential Kv1.2 Potassium Channel Blockers with New Skeletons from Chukrasia tabularis. Organic Letters 14 (17), 4438 – 4441.), belong to open first for the purposes of the Chukrasone A that the present invention relates in preparation treatment or preventing renal fibrosis medicine, because framework types belongs to brand-new framework types, and it suppresses active unexpectedly strong for renal fibrosis, there is not the possibility that is provided any enlightenment by other chemical compounds, possess outstanding substantive distinguishing features, the control that is used for simultaneously renal fibrosis obviously has significant progress.
Summary of the invention
The invention provides the application of Chukrasone A in the medicine of preparation prevention or treatment renal fibrosis.
Described Compound C hukrasone A structure is shown in formula I:
The purposes of the Chukrasone A that the present invention relates in preparation treatment or preventing renal fibrosis medicine belongs to open first, because framework types belongs to brand-new framework types, and it suppresses active unexpectedly strong for renal fibrosis, there is not the possibility that is provided any enlightenment by other chemical compounds, possess outstanding substantive distinguishing features, the control that is used for simultaneously renal fibrosis obviously has significant progress.
The specific embodiment
The preparation method of Compound C hukrasone A involved in the present invention is referring to document (Liu, H. B. et al., 2012. Chukrasones A and B:Potential Kv1.2 Potassium Channel Blockers with New Skeletons from Chukrasia tabularis. Organic Letters 14 (17), 4438 – 4441.).
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not subjected to any restriction of specific embodiment, but limited by claim.
Embodiment 1: the preparation of Compound C hukrasone A tablet involved in the present invention:
Get 20 and digest compound Chukrasone A, add conventional adjuvant 180 grams of preparation tablet, mixing, conventional tablet machine are made 1000.
Embodiment 2: the preparation of Compound C hukrasone A capsule involved in the present invention:
Get 20 and digest compound Chukrasone A, add conventional adjuvant such as starch 180 grams of preparation capsule, mixing is encapsulatedly made 1000.
Further specify its pharmaceutically active below by pharmacodynamic experiment.
Test Chukrasone A is on the impact of Rats Undergoing Unilateral Urethral Ligation kidney region fibrosis
1.1 material
Benazepril, Novartis Pharma AG produces; Hydroxyproline (HYP) test kit, biotech firm is built up in Nanjing; Fibronectin (FN) test kit is available from the Shanghai institute of Biological Products.
Laboratory animal: regular grade Wistar rat, male, body weight 150-200g, SD rat.
1.2 test method and result
90 of rats, divide at random 9 groups, it is sham operated rats, model group, benazepril gavage 10mg/kg group, Chukrasone A intravenous injection 2.5 mg/kg group, Chukrasone A intravenous injection 5 mg/kg group, Chukrasone A intravenous injection 25 mg/kg group, Chukrasone A gavage 5mg/kg group, Chukrasone A gavage 10mg/kg group, Chukrasone A gavage 50mg/kg group, 1 week of animal feeding, each rat with 10% chloral hydrate 3.0mL/kg intraperitoneal injection of anesthesia after, with the Rat Right lateral position fixing with operating-table on, use iodine tincture after the cropping, 75% alcohol disinfecting field of operation, row left side abdomen otch, successively cut skin, muscle and each layer of stomach wall, expose and separation left side ureter, sham operated rats is only cut abdominal cavity and free left side ureter, but not ligation and cutting off, other respectively organize rat 4-0 silk thread ligation twice, upper one ligation point is positioned at left inferior pole of kidney level, then cut off ureter at twice ligation point, layer-by-layer suture, postoperative was put to death each treated animal after 10% chloral hydrate anesthesia in 10 days, get blood, press Fibronectin and measure explanation mensuration explanation fiber connexin (FN).Normal saline is left and taken 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 and to be examined 1. perusal: sham operated rats kidney color is scarlet, shows smoothly, and peplos gloss is without adhesion.Other respectively organize the Kidney Volume increase, and color is pale, shows to be graininess, similar human body branny kidney, the adhesion of a few regions kidney peplos.2. light microscopy checking: the result is clear for the sham operated rats nephron, and glomerular capsule is without expansion or cell infiltration.The large stretch of renal tubular necrosis of model control group, the hyperplasia of kidney interstitial fibers, tubular ectasia, in a large amount of brown color shading materials or the downright bad epithelial cell that comes off are arranged, the glomerule decreased number, part glomerule fibrosis and with the adhesion of bowman's capsule wall, blister cavities disappears.Administration respectively organizes pathological changes and model control group is similar, but all has morphology in various degree to improve, and especially with heavy dose of each group of Chukrasone A gavage significantly, with model control group notable difference is arranged relatively.
Table 1 Chukrasone A is on the impact of Rats Undergoing Unilateral Urethral Ligation kidney region fibrosis
* p＜0.05, compare with model group in * * p＜0.01
Each group FN, HYP are carried out the T check.The results are shown in Table 1, Chukrasone A intravenous injection 5 mg/kg organize, Chukrasone A intravenous injection 25 mg/kg organize, Chukrasone A gavage 10mg/kg organizes, Chukrasone A gavage 50mg/kg group reduces FN, HYPP level (comparing P＜0.05 or 0.01 with model control group).
Conclusion: Chukrasone A can significantly reduce the rising of kidney region fibrosis FN, HYPP level, suppresses kidney region fibrosis, can be used for preparing anti-renal fibrosis medicine.
Claims (1)
1.Chukrasone the application of A in treatment or the medicine of preventing renal fibrosis, described Compound C hukrasone A structure as
Formula IShown in:
Formula I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310279831.2A CN103356659B (en) | 2013-07-04 | 2013-07-04 | The application of Chukrasone A in the medicine preparing treatment or preventing renal fibrosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310279831.2A CN103356659B (en) | 2013-07-04 | 2013-07-04 | The application of Chukrasone A in the medicine preparing treatment or preventing renal fibrosis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103356659A true CN103356659A (en) | 2013-10-23 |
| CN103356659B CN103356659B (en) | 2015-08-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310279831.2A Active CN103356659B (en) | 2013-07-04 | 2013-07-04 | The application of Chukrasone A in the medicine preparing treatment or preventing renal fibrosis |
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| Country | Link |
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| CN (1) | CN103356659B (en) |
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- 2013-07-04 CN CN201310279831.2A patent/CN103356659B/en active Active
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| Publication number | Publication date |
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| CN103356659B (en) | 2015-08-19 |
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Address after: Tiefu iron rich street Pizhou city 221331 Jiangsu city of Xuzhou Province Patentee after: Ding Shengyu Address before: 210009 Gulou District, Jiangsu, Nanjing Gu Ping Kong, No. 4 Patentee before: Ding Shengyu |
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Effective date of registration: 20181025 Address after: 510640 2414-2416 of the main building 371, five mountain road, Tianhe District, Guangzhou, Guangdong. Patentee after: Guangdong Gaohang Intellectual Property Operation Co., Ltd. Address before: 221331 Jiangsu province Xuzhou city Pizhou City Tie Fu town tie Fu Street Patentee before: Ding Shengyu |
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Effective date of registration: 20181101 Address after: 233000 Anhui Bengbu City Huaguang Avenue Jiahe residential area independent commercial building (two floor) Patentee after: Bengbu Zhongzhi Intellectual Property Operation Co., Ltd. Address before: 510640 2414-2416 of the main building 371, five mountain road, Tianhe District, Guangzhou, Guangdong. Patentee before: Guangdong Gaohang Intellectual Property Operation Co., Ltd. |
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