CN102755312A - Application of compound with flavone skeleton structure as Parkinsonism treating medicine - Google Patents
Application of compound with flavone skeleton structure as Parkinsonism treating medicine Download PDFInfo
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- CN102755312A CN102755312A CN2012102442021A CN201210244202A CN102755312A CN 102755312 A CN102755312 A CN 102755312A CN 2012102442021 A CN2012102442021 A CN 2012102442021A CN 201210244202 A CN201210244202 A CN 201210244202A CN 102755312 A CN102755312 A CN 102755312A
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- scutellarein
- flavone
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- levodopa
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Abstract
The invention relates to application of a compound with a flavone skeleton structure as a Parkinsonism treating medicine. The compound with a flavone skeleton structure is an inhibitor for the catechol methylation transferase; and the compound specifically comprises radix scutellariae, scutellarein and structure derivatives of radix scutellariae and scutellarein, and can be used as a synergist of the Parkinsonism treating medicine levodopa. In-vitro activity test indicates that IC50 of the compound in inhibiting catechol methylation transferase can reach nanomole level, wherein the COMT(Catechol O Methyl Transferase) inhibition activity of scutellarein and the derivatives of scutellarein is superior to that of medicine tolcapone on the market. The rat overall pharmacokinetic study shows that by the joint application of scutellarein and levodopa, the blood concentration of levodopa can be obviously increased. Moreover, the compound does not generate active intermediate through metabolism activation or form toxic adduct together with biological macromolecules, thus the hepatotoxicity and nephrotoxicity caused by metabolism activation are avoided, and the compound has good prospect of patent medicine.
Description
Technical field
The invention belongs to medical technical field, be specifically related to have of the application of the chemical compound of flavone framing structure as the Parkinson's disease medicine.
Background technology
(Parkinson's disease PD) is a kind of chronic central nervous system's degenerative imbalance that dopamine (Dopamine) deficiency causes in the brain to Parkinson's disease.After ill, patient's moving function, linguistic competence etc. are badly damaged, and with pain, and limbs are stiff, tremble etc., and symptom causes patient's quality of life seriously to descend.This sick sickness rate is up to 1.6%, and along with the increase at age, ill risk is also increasing [Neurology.2000; 54:S24-7].According to estimates, China is the maximum country of PD patient in the world, and [Lancet 2005 for existing at present patient 1,700,000; 365:595-7].Along with the arriving of aging society, problems such as the medical treatment that PD brings, family, society are extensive all the more and severe.At present, the efficacious therapy means of treatment PD are the dopamine alternative medicine, promptly in patient's brain, change dopamine into through prodrug levodopa (L-dopa), with insufficient dopamine [EurNeurol.2009 in additional patient's brain; 62:1-8].It should be noted that L-dopa has only the brain competence exertion effect that arrives, but since L-dopa in peripheral tissues very easily by metabolism, almost do not have drug effect when using separately.Methylating of catechol O-methyltransferase (COMT) mediation is the main metabolic pathway that L-dopa takes place, and clinical research has confirmed that COMT enzyme inhibitor and L-dopa coupling really can strengthen curative effect [the Pharmacol Rev.1999 of L-dopa; 51:593-628].Therefore, develop that the COMT enzyme inhibitor is most important for the Drug therapy of Parkinson's disease efficiently.
Yet; The COMT enzyme inhibitor that has gone on the market (like tolcapone, grace tolcapone) is mainly deposited many defectives such as inhibition activity in vivo is on the low side, metabolic half life is short, the easy initiation of continuous use liver, nephrotoxicity; Parkinson's disease patients then needs frequent medication, can cause serious adverse effects [Neurology2004 behind the existing COMT enzyme inhibitors such as life-time service tolcapone, grace tolcapone; 62:39-46].Therefore development of new safely and effectively the COMT inhibitor be the task of top priority that has become current Parkinson's disease medicine development field.
(Catechol-O-methyltransferase COMT) is a kind of magnesium ion dependent form enzyme to the catechol methylated transferase, and it as the methylating of methyl donor catalysis pyrocatechol substrate, generates the corresponding O-catechol that methylates with SAM.The COMT enzyme has two kinds of existence forms at human body: film grappling type and free type.Mainly exist in the peripheral tissues of human body, but be main with film grappling type COMT enzyme at brain with free type COMT enzyme.The COMT enzyme of two kinds of existence forms is almost consistent on aminoacid sequence, but with the affinity of substrate on show bigger difference.Ideal COMT enzyme inhibitor should be only has the COMT that stronger inhibition ability does not get into brain inhibition maincenter tissue simultaneously to the free type COMT enzyme of human body peripheral distribution; Slow down the methylate metabolism of L-dopa thereby play, the metabolism that methylates of endogenous neurotransmitter in the maincenter of the not influence simultaneously tissue in peripheral tissues.Utilize that strong to imitate the action time that periphery COMT enzyme inhibitor improves the oral administration biaavailability of L-dopa and prolong L-dopa be the first-selection of current clinical treatment Parkinson's disease.Therefore, new type of safe, to imitate the exploitation of catechol methylated transferase inhibitor by force most important for the treatment of Parkinson's disease.
Summary of the invention
The purpose of this invention is to provide the application of chemical compound with flavone framing structure as the Parkinson's disease medicine; The chemical compound of this flavonoid framing structure is catechol methylated transferase (COMT enzyme) inhibitor, and the synergist that such inhibitor can be used as Parkinson's disease medicine levodopa uses.
The invention provides the application of chemical compound with flavone framing structure as the Parkinson's disease medicine; The chemical compound of this flavonoid framing structure is a catechol methylated transferase inhibitor; Specifically comprise baicalin, scutellarein and structural derivative thereof; Such strong COMT enzyme inhibitor of imitating has flavone skeleton and catechol group, and general structure is as shown in Figure 1, R
1Be hydrogen, hydroxyl or methoxyl group substituent group; R
2Be hydrogen, nitro, aldehyde radical or cyanic acid substituent group; R
3Be hydrogen, hydroxyl or glucuronic acid substituent group.
The present invention is directed to the number of drawbacks (suppress active use on the low side, continuous in the body and be prone to cause liver, nephrotoxicity etc.) that existing COMT enzyme inhibitor exists, from the natural Chinese medicine chemical constituent, filter out the lead compound of high security and obtained new and effective, safe flavone pyrocatechol COMT enzyme inhibitor through becoming property of medicine optimization to transform on this basis.
Application with chemical compound of flavone framing structure as the Parkinson's disease medicine provided by the invention; Such inhibitor monomer is united use with Parkinson's disease medicine (levodopa, carbidopa/levodopa) after can becoming dosage form separately, processes tablet, slow releasing tablet, capsule, drop pill after can flavone catechol monomer and preparation adjuvant commonly used being mixed.Also can with Parkinson's disease medicine (levodopa, carbidopa/levodopa) proportional mixing after form dosage forms such as tablet, slow releasing tablet, capsule, drop pill and use as pharmaceutical composition.Ratio when catechol methylated transferase inhibitor mixes use with levodopa is between 1:5-5:1.
The flavone pyrocatechol COMT enzyme inhibitor that the present invention relates to; The intravital metabolite of this flavonoid catechol people still has the catechol methylated transferase and suppresses active, and its metabolite still can be brought into play the purposes of Parkinson's disease medicine synergist in vivo.
The advantage of the flavone pyrocatechol COMT enzyme inhibitor that the present invention relates to is following:
1. safe, this compounds does not have overt toxicity to human body main organs cell, and can not produce reactive intermediate through metabolic activation, can not form the toxicity adduct with biomacromolecule;
2.COMT enzyme inhibition activity is high, its half-inhibition concentration IC
50Can reach the nM level, after PK research showed itself and L-dopa coupling in the body, the AUC of L-dopa is the highest to increase by 57%;
3. this compounds is difficult for penetrating blood brain barrier, can the interference maincenter in the metabolism that methylates of endogenous neurotransmitter;
4. the glucuronic acid metabolite of this compounds still has the COMT enzyme inhibition activity.
Description of drawings
The general structure of Fig. 1 flavone pyrocatechol COMT enzyme inhibitor;
Fig. 2 baicalin is to COMT enzyme depression effect figure;
Fig. 3 scutellarein is to COMT enzyme depression effect figure.
The specific embodiment
Below in conjunction with embodiment the present invention is further specified, but therefore do not limit the present invention.
Embodiment 1. flavone pyrocatechol series compounds are to the inhibition determination of activity of COMT enzyme
With the protocatechuic acid methylation reaction is probe reaction, by the outer incubation system of human liver cell slurry, measures the IC that the pyrocatechol series compound suppresses the COMT enzyme
50, concrete experiment flow is following:
In the external metabolic response system of (1) 200 microlitre, add 5mM MgCl
2, the 2mM dithiothreitol, DTT, 0.2mM S-ademetionine, human liver cell slurry protein concentration is 1mg/ml, inhibitor final concentration scope is 0.01 μ M-1 μ M, under 37 ℃ of conditions, incubates in advance 3 minutes;
(2) in reaction system, add substrate (final concentration 15uM), initial action; Add 200 μ l acetonitriles in reaction under 37 ℃ of conditions after 30 minutes, behind the concuss, cessation reaction;
(3) adopt High speed refrigerated centrifuge, under the condition of 20,000 * g, the above-mentioned system of high speed centrifugation was got supernatant after 15 minutes, carried out the HPLC-UV check and analysis; Under 259nm, the protocatechuic acid metabolite is carried out detection by quantitative through ultra-violet absorption spectrum.
This compounds demonstrates the dependent inhibition of substrate to the COMT enzyme, and Lineweaver-Burk and Dixon mapping show that all this compounds is the noncompetitive inhibitor of COMT enzyme.The half-inhibition concentration of each chemical compound is as shown in table 1, can find out that therefrom flavone pyrocatechol series compound has stronger inhibition active to the COMT enzyme, and the inhibition activity of most chemical compounds is superior to tolcapone.
Table 1
The assessment of embodiment 2. flavone pyrocatechol series compound metabolic activations
In the people's hepatomicrosome incubation system that adds cofactor NADPH or its generation structure; Add each flavone pyrocatechol series compound (final concentration is 100 μ M) and reduced glutathion (final concentration is 1000 μ M) respectively; After hatching 120 minutes under 37 ℃; With isopyknic acetonitrile cessation reaction, whether centrifugal have active adduct to be caught in except that carrying out the adduct detection by AB Qtrap5500 after the Deproteinization, detecting.The result is as shown in table 2.
Table 2
Therefrom can find out to have only that the marketed drug tolcapone can produce active adduct, flavone pyrocatechol series compound does not then detect active adduct.This compounds of this results suggest can not produce reactive intermediate through metabolic activation, can not form the toxicity adduct with biomacromolecule, therefore can be because of metabolic activation does not cause liver, nephrotoxicity, and safety is good.
The whole pharmacokinetics research of embodiment 3. scutellarein and L-dopa coupling
Select 18 Wistar rats; Male and female half and half; Be divided into 3 groups at random by body weight (180-220g), 6/group is carried out the whole pharmacokinetics research of independent oral L-dopa and oral scutellarein of while and L-dopa, and influence compares to the L-dopa pharmacokinetics with positive control (tolcapone).Respectively before gathering administration after blood plasma and the administration about 5,10,15,30,60,120,180,240 minutes rat plasma sample 0.5ml; Place the brown centrifuge tube in the 1.5ml point end of heparinization in advance; Behind centrifugal 10 minutes of 4000 * g; (20,000 * g), it is to be measured to go supernatant to be stored in-80 ℃ of refrigerators to add isopyknic methanol extraction albumen and high speed centrifugation after the separated plasma.Adopt UFLC-ESI-MS to measure the blood drug level of L-dopa in each sample, use DAS2.0 software the blood drug level data are handled, and calculate pharmacokinetic parameters.The result shows; With respect to positive control (tolcapone), scutellarein can significantly improve L-dopa level in the rat plasma, and its AUC has increased 57%; Simultaneously the internal metabolism half-life has prolonged 1.8 times, and above result shows that scutellarein brought into play the effect of L-dopa synergist.
Claims (4)
1. have the application of the chemical compound of flavone framing structure as the Parkinson's disease medicine, it is characterized in that: this compounds is a catechol methylated transferase inhibitor, and its general structure is following:
Wherein, R
1Be hydrogen or hydroxyl substituent; R
2Be hydrogen or nitro substituent; R
3Be hydrogen, hydroxyl or glucuronic acid substituent group.
2. according to the described application of claim 1 with chemical compound of flavone framing structure as the Parkinson's disease medicine; It is characterized in that: said inhibitor share with Parkinson's disease medicine levodopa behind the patent medicine separately, also can with make pharmaceutical composition after Parkinson's disease medicine levodopa mixes by a certain percentage and use.
3. according to the described application with chemical compound of flavone framing structure as the Parkinson's disease medicine of claim 1, it is characterized in that: the mol ratio of catechol methylated transferase inhibitor and levodopa is between 1:5-5:1 in the said pharmaceutical composition.
4. according to the described application with chemical compound of flavone framing structure as the Parkinson's disease medicine of claim 1, it is characterized in that: this inhibitor can be made tablet, slow releasing tablet, capsule, drop pill use when using.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103919765A (en) * | 2014-04-24 | 2014-07-16 | 无锡艾德美特生物科技有限公司 | Application of hispidulin in preparing catechol drug synergist and pharmaceutical composition containing hispidulin |
| CN104277081A (en) * | 2013-07-05 | 2015-01-14 | 中国科学院大连化学物理研究所 | Hydroxy cinnamic acid amine compounds and preparation and application thereof |
| CN105315251A (en) * | 2014-06-24 | 2016-02-10 | 中国科学院大连化学物理研究所 | Application of oroxylin A and pro-drug thereof as catechol-type medicine synergist |
| US9458128B2 (en) | 2012-05-24 | 2016-10-04 | Orion Corporation | Catechol O-methyltransferase activity inhibiting compounds |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9458128B2 (en) | 2012-05-24 | 2016-10-04 | Orion Corporation | Catechol O-methyltransferase activity inhibiting compounds |
| CN104277081A (en) * | 2013-07-05 | 2015-01-14 | 中国科学院大连化学物理研究所 | Hydroxy cinnamic acid amine compounds and preparation and application thereof |
| CN104277081B (en) * | 2013-07-05 | 2017-03-29 | 中国科学院大连化学物理研究所 | A kind of hydroxycinnamic acid aminated compoundss and its preparation and application |
| CN103919765A (en) * | 2014-04-24 | 2014-07-16 | 无锡艾德美特生物科技有限公司 | Application of hispidulin in preparing catechol drug synergist and pharmaceutical composition containing hispidulin |
| CN103919765B (en) * | 2014-04-24 | 2016-06-15 | 无锡艾德美特生物科技有限公司 | Dinatin application in preparation catechol medicament synergistic agent and comprise the pharmaceutical composition of dinatin |
| CN105315251A (en) * | 2014-06-24 | 2016-02-10 | 中国科学院大连化学物理研究所 | Application of oroxylin A and pro-drug thereof as catechol-type medicine synergist |
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Application publication date: 20121031 |