CN101830878B - Polymethoxyflavonoids (PMFs) and derivative as medicaments for preventing and treating atrial fibrillation (AF) and using method - Google Patents
Polymethoxyflavonoids (PMFs) and derivative as medicaments for preventing and treating atrial fibrillation (AF) and using method Download PDFInfo
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- CN101830878B CN101830878B CN2010101841311A CN201010184131A CN101830878B CN 101830878 B CN101830878 B CN 101830878B CN 2010101841311 A CN2010101841311 A CN 2010101841311A CN 201010184131 A CN201010184131 A CN 201010184131A CN 101830878 B CN101830878 B CN 101830878B
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Abstract
The invention discloses polymethoxyflavonoids (PMFs) and a derivative as medicaments for preventing and treating atrial fibrillation (AF) and a using method. Aiming at a high risk population with AF or a patient confirmed to suffer from AF, the AF can be prevented or/and treated by adopting the PMFs with effective dosage and the derivative or a compound preparation containing the substances.
Description
Technical field
The invention belongs to field of medicaments, relate to PMFs and verivate medicine and usage as prevention and treatment AF.
Background technology
AF is common arrhythmia in clinic type (Burashnikov, A.&Antzelevitch, C.Nat.Rev.Cardiol.2010; 7:139-148), its sickness rate and hazardness all are and increase trend.Although the radio-frequency ablation procedure of ring pulmonary artery sleeve has the improvement effect to paroxysmal AF; But the first-line treatment of keeping the rhythm of the heart remains the use anti-arrhythmic; Right existing anti-AF medicine or curative effect are not good enough, or spinoff obvious (comprising intracardiac outer with the heart), even can bring out the mortality ventricular arrhythmia.Based on research to the pathophysiological mechanism of AF, think that at present ionic channel and the electric current in the time of can not only being confined to AF changes, should pay close attention to correlative factor comprehensively, see Fig. 2.
To the progress of AF pathophysiological mechanism, for researching and developing anti-AF medicine possible novel targets and new link is provided, thereby made the research direction of anti-AF medicine of new generation gradually clear, see Fig. 3.
Based on the understanding to novel targets, the New Policy of anti-AF medicament research and development is following:
1, selectivity suppresses the atrium ionic channel: by the I of Kv1.5 mediation
KurOnly be present in the atrium, I
KAChBe advantage distributes in the atrium.If drug selectivity suppresses I
KurAnd I
KACh, while appropriate inhibition hERG, I
NaAnd I
Ca, just hope again to produce specific anti-AF effect, satisfy the 1st type " selectivity target spot " among Fig. 3.
2, suppress chronic inflammatory diseases: in the chronic inflammatory diseases process; Produce many inflammatory factors; Like IL-6, TNF-α etc., these inflammatory factors are participated in the pathologic structural remodeling and the electric reconstruct of heart on the one hand, also participate in generation and the development (Fig. 2) bringing out and increase the weight of AF on the other hand directly.Like inflammation-inhibiting, satisfy the 2nd type among Fig. 3.
3, anti-oxidation stress property damage: the formation of AF is also participated in the damage of oxidative stress property, thus there is anti-oxidation medicine can improve AF, like Statins lipid regulating agent, vitamin E etc.
4, resisting cardiac hypertrophy, anti-cardiac remodeling: the atrium pathologic reconstruct that a variety of causes causes is the organization foundation that AF takes place, and anti-cardiac remodeling medicine can improve AF, like ACEI inhibitor, angiotensin ii receptor antagonist (AT
1Retarding agent) AF of improvement effect is all arranged.
5, suppress to connect albumen: suppress to connect PROTEIN C x40, Cx43, also can improve AF.
Although placing hope on selectively acting atrium ionic channel (mainly is that selectivity suppresses I
KurAnd I
KACh) medicine, do not appear on the market but still there is medicine so far.In view of the complicacy of AF, we think the anti-AF medicine of ideal should be able to be to too many levels, many target spots, carry out effectively direct and indirect comprehensive intervention.
As possess in the above-mentioned strategy several or all simultaneously, and will be fully novel, as to have DEVELOPMENT PROSPECT anti-atrial fibrillation medicine, be worth striving to find.
Known poly-hydroxy Flavonoid substances (containing a plurality of phenolic hydroxyl groups) pharmacological action is extensive, comprising: antioxidant stress injury, improve blood vessel inner skin cell function, vasodilator, bring high blood pressure down, anti-inflammatory, atherosclerosis, arrhythmia, fat-reducing, hypoglycemic, improve insulin resistant, improve hyperlipemia, improve hemorheology properties, antitumor, anti-multidrug resistance etc.But poly-hydroxy flavone oral bioavailability extreme difference is the biggest obstacle that such material is difficult to become medicine.
Summary of the invention
The present invention proves that PMFs and verivate are one type of brand-new anti-AF medicines, but relative selectivity ground carries out the comprehensive intervention of too many levels, many target spots to AF.
The PMFs good stability, bioavailability is high, and above-mentioned effect is more outstanding.Our discover PMFs and verivate can improve AF through the effect to a plurality of target spots.PMFs is present in root, stem, leaf, flower and the fruit of various plants, but content is less relatively, and extraction process does not have important breakthrough so far, must measure very littlely, makes experimental study be difficult to carry out, and it is out of reach that drug development more shows.We once successfully utilized Quercetin to prepare the pentamethyl-Quercetin, made its technology reach industrialized level (Yang Fei, the golden language of the Manchus etc.: utilize Quercetin to prepare the method for pentamethyl-Quercetin, patent publication No.: CN101270109 (A)).Based on the successful experience that this laboratory methylates and modifies the poly-hydroxy flavones, we utilize commercially available poly-hydroxy flavones successfully to synthesize a series of PMFs, and the production technique that the PMFs of property of medicine prospect is wherein arranged into has reached the pilot scale level, sees Fig. 4.Be exemplified below:
The present invention is intended to polymethoxyflavone class material and the verivate medicine as prevention and treatment AF, and recommends the phase application method.
Summary of the invention 1:PMFs and verivate obviously suppress I
KurAnd I
KACh, slightly suppress other positive-ion currents (like hERG, INa, Ito and I
Kr), specificity prolongs atrium ERP and APD, produces direct anti-AF effect.Specificity prolongs atrium ERP and APD, at the dosage range that influences the ventricular muscles electrophysiological characteristics hardly, produces good anti-AF effect.
Synthetic and the release of the obvious inflammation-inhibiting vitamin T of summary of the invention 2:PMFs and verivate NF-α and IL-6 obviously increases the synthetic and release of anti-inflammatory factors adiponectin, thereby produces anti-inflammatory action, participates in direct and indirect anti-AF effect.
Summary of the invention 3:PMFs and verivate have tangible antioxygenation, help stopping AF.
Summary of the invention 4:PMFs resisting cardiac hypertrophy improves pathologic reconstruct.
Description of drawings
Fig. 1. the substruction I of polymethoxyflavone class and verivate
The pathophysiological mechanism that Fig. 2, atrial fibrillation take place.Relation between inflammation, electric reconstruct and the structural remodeling reaches the common influence to AF.
Fig. 3. the research direction of anti-AF medicine of new generation and target spot (or strategy) classification.Target spot 3 and 4 effects are barely satisfactory.Target spot 1 and 2 is present hope places.
Fig. 4. with the apigenin is raw material, synthesization of dimethyl apigenin, 5-phenoxybutyldimethyl,piolin (5-benzene oxygen butoxy-7,4 '-dimethoxy flavone; Code name TJ-430, the abbreviation 5-PB-DMA), trimethylammonium apigenin (5,7; 4 '-trimethoxy flavones, code name TJ-431, abbreviation TMA).
Fig. 5 .5-benzene oxygen butoxy-7,4 '-dimethoxy flavone (code name TJ-430 or abbreviation 5-PB-DMA) is to the inhibition of IKur (hKv1.5).Show voltage-dependent (it is stronger that positive potential suppresses) and frequency dependence (it is stronger that high frequency suppresses).This effectiveness is favourable to treatment AF ten minutes, is one of main direction of seeking at present the anti-AF medicine of selectivity.
Fig. 6 .5-benzene oxygen butoxy-7,4 '-dimethoxy flavone (TJ-430 or 5-PB-DMA) is to I
NaInhibition.TJ430 (3 μ M) slightly suppresses I
Na(16% ,-30mV), can strengthen suppressing the AF effect.
Fig. 7 .5-benzene oxygen butoxy-7,4 '-dimethoxy flavone (TJ-430 or 5-PB-DMA) has restraining effect to IKr (hERG), but not as so strong to IKur (Kv1.5). can strengthen suppressing the AF effect, and be unlikely to cause ventricular arrhythmia.
Fig. 8 .5-benzene oxygen butoxy-7,4 '-dimethoxy flavone (TJ-430 or 5-PB-DMA) is to the inhibition of Ito (hKv4.3).Display frequency dependency (it is stronger that high frequency suppresses).This effectiveness is favourable to treatment AF.
Fig. 9 .5,7,4 '-trimethoxy flavones (code name TJ-431, abbreviation TMA) concentration dependent ground suppresses people's heart muscle I
Kur, IC
50Be 8 μ M.Point out it selectivity to improve AF.
Figure 10 .5,7, (TJ-431 TMA) suppresses rat atrial flesh I to 4 '-trimethoxy flavones
KACh, IC
50Be 6.8 μ M.Point out it selectivity to improve AF.
Figure 11 .5,7,4 '-trimethoxy flavones (TJ-431, TMA) concentration dependent ground suppress the 3T3-L1 cell TNF-α (on) with IL-6 (descending) expression.
Figure 12 .5,7, (TJ-431 is TMA) in the anti-oxidative damage effect of cardiac muscle for 4 '-trimethoxy flavones.Last figure is in the neonatal rat myocardial cell experiment of cultivating, and obviously reduces H
2O
2Damaging action, increase myocardial cell's survival; Figure below is to irritate heart again at the anesthetized rat ischemic, and TMA sees obvious increase SOD active (left side) when dwindling infarct size, reduce MDA content (right side).
Figure 13 .5,7,4 '-trimethoxy flavones (TJ-431, TMA) 5mg/kg/d, 14 days, the influence of the rat heart reconstruct that Ang II is caused.Last figure: TMA reduces the organ index of heart; The heart collagen that figure below: TMA minimizing AngH causes increases.
Embodiment
The present invention is with 5-benzene oxygen butoxy; 7; 4 '-dimethoxy flavones, 5,7,4 '-the trimethoxy flavones is an example; Studied the influence of such material to the 1st and the 2nd liang of sport index of " research direction of anti-AF medicine of new generation " shown in Figure 3, promptly " atrium selectivity or specificity target spot " reaches the many parameters in " upper reaches treatment target spot ".Our research confirms: such material can optionally influence the distinctive ionic channel in atrium (embodiment 1～2); Have the upper reaches factor (embodiment 3～5) that AF forms of participating in of improving again concurrently; By this, we think that material involved in the present invention is complete novel anti-FA medicine.
Embodiment 1:5-benzene oxygen butoxy, 7,4 '-dimethoxy flavone (code name TJ-430 or abbreviation 5-PB-DMA) ionic channel (electric current) Kv1.5, Nav1.5, the hERG relevant to AF, and I
To(Kv4.3) its specificity to the atrium effect is pointed out in inhibition (Fig. 5-8).Satisfy the 1st index among Fig. 3.
Embodiment 2: the present invention proves another PMFs class material 5,7, and 4 '-trimethoxy flavones (code name 431 or abbreviation TMA) is to atrium IKur and I
KAChRestraining effect also arranged.Prompting is the general character of such material to the selectively acting in atrium.
Fig. 9-the 10th, TMA is to the restraining effect of people's heart muscle IKur and rat atrial flesh IKAch.IC
50Be respectively 8 and 6.8 μ M.IKur and IKACh all be heart muscle peculiar, with AF closely-related ionic channel takes place, TMA obviously suppresses IKur and I
KAChSupport it can produce selectively acting to the atrium.
Embodiment 3:5,7,4 '-trimethoxy flavones (TJ-431, TMA) inflammation-inhibiting factor expression.Inflammatory factor TNF-α and IL-6 are mainly from fatty tissue, and we utilize the 3T3-L1 cell model, prove that TMA concentration dependent ground suppresses TNF-α and IL-6 expresses.Figure 11 .5,7,4 '-trimethoxy flavones (TJ-431, TMA) concentration dependent ground suppress the 3T3-L1 cell TNF-α (on) with IL-6 (descending) expression.
Embodiment 4:5,7,4 '-(TJ-431 TMA) has tangible anti-oxidative damage effect to the trimethoxy flavones.At the rat neonatal rat myocardial cell of cultivating, TMA obviously resists the oxidative damage of H2O2, increases the survival of cell.At anesthetized rat ischemic-irritate again heart and injury model, irritate stomach and give the TMA pre-treatment 1 week, can obviously dwindle myocardial infarction area, improve heart function, seeing simultaneously that SOD of heart tissue is active improves, and myocardium MDA content reduces.Figure 12 .5,7, (TJ-431 is TMA) in the anti-oxidative damage effect of cardiac muscle for 4 '-trimethoxy flavones.Last figure is in the neonatal rat myocardial cell experiment of cultivating, and obviously reduces H
2O
2Damaging action, increase myocardial cell's survival; Figure below is to irritate heart again at the anesthetized rat ischemic, and TMA sees obvious increase SOD active (left side) when dwindling infarct size, reduce MDA content (right side).
Embodiment 5:5,7,4 '-the trimethoxy flavones (TJ-431, TMA) have tangible resisting cardiac hypertrophy, improve the effect of cardiac remodeling.Injection Ang II 288 μ g/kg/d, continuous 7 days, bring out rat heart reconstruct, (cardiac weight/body weight (mg/g) increases, collagen is synthetic increases to show as cardiac index.Irritate stomach and give TMA 5mg/kg/d, finish totally 14 days from modeling beginning in preceding 7 days to experiment.TMA obviously reduces cardiac index, reduces I type and III Collagen Type VI amount, points out it to improve cardiac fibrosis, improves cardiac remodeling.Figure 13 .5,7,4 '-trimethoxy flavones (TJ-431, TMA) 5mg/kg/d, 14 days, the influence of the rat heart reconstruct that Ang II is caused.Last figure: TMA reduces the organ index of heart; The heart collagen that figure below: TMA minimizing AngH causes increases.
Embodiment 6:5-benzene butoxy, 7,4 '-dimethoxy flavone (5-PB-DMA, TJ-430) with 5,7,4 '-(TJ-431 TMA) has tangible anti-experimental character AF effect to the trimethoxy flavones.
1, anesthesia Beagle dog, abdominal injection 5-PB-DMA (TJ-430,10mg/kg) or TMA (TJ-431 20mg/kg) does not have obvious influence to heart rate, does not influence QTc.
2, anesthesia Beagle dog; Stimulate the bilateral vagus nerve to bring out AF model (ventricle constant speed pace-making is kept heart function), and abdominal injection 5-PB-DMA (TJ-430,10mg/kg) or TMA (TJ-431; 10mg/kg) can obviously improve threshold of ventricular fibrillation current (stimulus intensity of AF is brought out in increase), shorten the AF time length.
Claims (1)
1.5,7,4 '-the trimethoxy flavones is used for preventing and treating the application of atrial fibrillation medicine in preparation.
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| Title |
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| Ju-Mi Jeong,et al..Antioxidant and Chemosensitizing Effects of Flavonoids with Hydroxy and/or Methoxy Groups and Structure-Activity Relationship.《J. Pharm. Pharmaceut. Sci.》.2007,第10卷(第4期),537－546. * |
| 向红琳,等.芹菜素醚化及溴化衍生物的合成及肝癌活性研究.《湖南师范大学学报(医学版)》.2009,第6卷(第3期),26-29. * |
| 王海娣，等.芹菜素药理作用的研究进展.《中国新药杂志》.2008,第17卷(第18期),1561－1565. * |
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