CN103655557A - Use of CD38 enzyme inhibitor in treating bronchial hyperresponsiveness diseases - Google Patents
Use of CD38 enzyme inhibitor in treating bronchial hyperresponsiveness diseases Download PDFInfo
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Images
Abstract
The invention relates to a medicament for treating bronchial hyperresponsiveness diseases, which is 5-(3-phenyl propionyl amino)-N-(4-carbethoxy phenyl)-1H-3-indole formamide. The medicament is a CD38 enzyme inhibitor which can relax tracheal smooth muscles by inhibiting Ca<2+> release, so that bronchial hyperresponsiveness diseases can be treated in a symptomatic manner; a mouse airway hyperresponsiveness model is manufactured by utilizing ozone, and meanwhile, an emulsifier of the medicament is given for gavage treatment, so that airway resistance of the mouse treated by the medicament is obviously lowered, dynamic lung compliance is obviously increased, and lung lesion degree is relieved; besides, the experiment finds that the medicament further has anti-inflammatory effect, anti-oxidization effect, no obvious toxic and side effect, has good development value, and belongs to the field of medicaments.
Description
Technical field:
The present invention relates to a kind of medicine for the treatment of airway hyperreactivity disease, 5-(3-phenyl propionamido)-N-(4-carbethoxy phenyl)-1H-3-indole carboxamides.This medicine is a kind of CD38 enzyme inhibitor, mainly by expanding tracheal smooth muscles, reaches therapeutic purposes, has antiinflammatory, antioxidation simultaneously, belongs to drug world.
Background technology:
Airway hyperreactivity refers to that trachea, bronchus itself are to various stimulations, comprises that specific antigen stimulates and nonspecific stimulation, as physics, chemical stimulation, presents overreaction, is the key character that branchial asthma patients is different from normal person
[1].Although the risk factor of airway hyper-reaction is varied, and the therapeutical effect link of various medicines is different, the research of new therapy is also multidirectional, substantially from antiinflammatory, antihistaminic, anaphylaxis medium sustained-release agent, corresponding suiting the medicine to the illness
[2]and Chinese medicine
[3]set out.At present, researcher is used more airway hyper-reaction model for the large and small mouse model of egg protein (OVA) sensitization, but the weak point of this modeling method is that the modeling time is long, success rate is not high and complicated operation.Due to the impact of industry and automobile exhaust gas, especially in big city, agricultural are around regional, and surface ozone can form and assemble.Surface ozone is to human body, and especially to eyes, respiratory tract etc. have erosion and detrimental effect.There is Many researchers from ozone, the infringement of man and animal and environmental conservation angle to be studied ozone both at home and abroad, find that ozone can not only increase the weight of respiratory system disease, also find that the ozone in air pollutants is directly related with asthma attack
[4-7].As far back as calendar year 2001, the domestic rabbit bronchial epithelial cell that just has researcher to utilize ozone aggressinogen culture, the antioxidant activity of observation bronchial epithelial cell
[8].The Zhang Jiansong of Hunan Normal University etc.
[9]utilize ozone to make the high reaction model of rat airway, and with the rat model comparison of egg protein (OVA) sensitization, find that ozone sucks the method for the unmanifest property airway hyperreactivity rat model of preparation simple and easy and feasible.This seminar's current research finds that the rat airway mucous secretion of ozone modeling obviously reduces after dexamethasone in treatment, the raw index of airway epithelia mucus deposit exponential sum goblet cellization is decreased significantly
[10].CD38 developed by molecule is quite extensive with distribution, and main lymphoid cell of expressing in jejune hematopoietic cell and activation, also has expression at skeletal muscle, cardiac muscle, airway smooth muscle and uterine smooth muscle CD38 molecule.The cADPR (cyclic adenosine diphosphate ribose, cADPR) that enzyme catalysis by CD38 molecule generates regulates Ca in cell
2+release and regulate cellular contraction
[11-13].The contractility of airway smooth muscle is mainly fixed against Ca in smooth muscle cell
2+concentration, CD38 molecule can regulate Ca in cell
2+concentration so that affect the contraction of airway smooth muscle, in the pathogenesis of asthma, play very important effect
[14].Inventor has synthesized two kinds of CD38 enzyme inhibitors, makes emulsifying agent, and the airway hyper-reaction mouse model that gavage treatment ozone causes, carries out pharmaceutical research, has completed the present invention.
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Summary of the invention:
The present invention seeks to study two kinds of CD38 enzyme inhibitors [3-carbamoyl-1-((2-(3-phenoxy-phenoxy) ethyoxyl) methyl) pyridine and 5-(3-phenyl propionamido)-N-(4-carbethoxy phenyl)-1H-3-indole carboxamides], be used for the treatment of airway hyperreactivity disease.
Inventor be take known CD38 crystal structure as basis, adopts the strategy of step-sizing to carry out virtual screening to commercial micromolecule data base (Sigma and Maybridge).The compound obtaining is taking into full account on the reasonability of binding pattern and the basis of structure diversity, buys wherein 23 compounds, has carried out CD38NADase and has suppressed active testing.According to the result of active testing and novel structure, synthetic difficulty, can be derivative etc. factor, selected primer.By repeatedly transformation and active testing to primer structure, finally obtain two kinds of CD38 enzyme inhibitors.
Inventor finds through research, 5-(3-phenyl propionamido)-N-(4-carbethoxy phenyl)-1H-3-indole carboxamides is except passing through to suppress CD38 enzymatic activity, outside expanding tracheal smooth muscles symptomatic treatment airway hyperreactivity disease, also there is antiinflammatory, antioxidant activity.In the middle of the present invention, by the high reaction model of airway of mice that uses ozone to make, inventor has studied the pharmacological action of these two kinds of CD38 enzyme inhibitors, finds that a kind of compound 5-(3-phenyl propionamido)-N-(4-carbethoxy phenyl)-1H-3-indole carboxamides wherein can obviously reduce airway of mice resistance, increases dynamic lung compliance, alleviate lung lesion degree; In addition, experiment finds that this medicine also has antiinflammatory, antioxidation, does not find obvious toxic-side effects.
Medicine of the present invention is yellowish white powder, and fusing point 192-194 ℃ is dissolved in DMF, acetone, is slightly soluble in methanol, dichloromethane, water insoluble, under strong acid, highly basic exist, decomposes.Medicine of the present invention can also contain applicable clinically pharmaceutical excipient.Its dosage form can be to be applicable to clinical various regular dosage forms, such as pill, tablet, powder, oral liquid, injection etc.
Accompanying drawing explanation:
Fig. 1: the structural formula of compound T;
Fig. 2: leukocyte count in BALF;
* P < 0.05 vs Normal group # P < 0.05 VS model group
P=0.090 VS model group P=0.068 VS model group (n=9～10)
Fig. 3: MDA content in BALF;
* P < 0.01 vs Normal group # P < 0.01 VS model group (n=9～10)
Fig. 4: each organizes the HE colored graph (* 100 times) of the dirty pathological section of mouse lung;
Fig. 5: each organizes the HE colored graph (* 400 times) of the dirty pathological section of mouse lung.
The specific embodiment:
Embodiment mono-: compound T[5-(3-phenyl propionamido)-N-(4-carbethoxy phenyl)-1H-3-indole carboxamides] physicochemical property
As shown in Figure 1, molecular weight is 455.51 to the structural formula of compound T, yellowish white powder, and fusing point 192-194 ℃, is dissolved in DMF, acetone, is slightly soluble in methanol, dichloromethane, water insoluble, under strong acid, highly basic exist, decomposes.Its dissolubility and ph stability can be by experimental results show that below.
1, dissolubility test
The dissolubility of object: test compounds T in different solvents
Principle: in the time of 20 ℃, the amount of the solvent of the dissolving in 100g solvent is that 1～10g is solvable, and 0.01g-1g is slightly soluble, and 0.01g is indissoluble below.In quantitative sample, add a certain amount of solvent, observe dissolving situation.
Method: get 2mg sample, add solvent concussion, clear is considered as dissolving completely without solid.
Slightly soluble and soluble demarcation line are that can 2mg sample be dissolved in 200mg solvent, and can the insoluble and sl. sol. 2mg of dividing into sample be dissolved in and being less than in 20g solvent.Therefore, in 2mg sample, add from small to large 200mg, 2g, 20g solvent until dissolving situation is observed in dissolving, record between the dissolve area of sample.
Result: the dissolving situation of 2mg sample in 200mg methanol is: can not dissolve completely; The dissolving situation of 2mg sample in 200mg methanol is: dissolve completely; The dissolving situation of 2mg sample in 200mg dichloromethane is: can not dissolve completely; The dissolving situation of 2mg sample in 2g dichloromethane is: dissolve completely; The dissolving situation of 2mg sample in 200mg acetone is: dissolve completely; The dissolving situation of 2mg sample in 200mg ethyl acetate is: can not dissolve completely; The dissolving situation of 2mg sample in 2g ethyl acetate is: dissolve completely; The dissolving situation of 2mg sample in 200mg DMF is: dissolve completely; The dissolving situation of 2mg sample in 20g water is: not exclusively dissolve.
Conclusion: compound T is dissolved in DMF, acetone, is slightly soluble in methanol, dichloromethane, ethyl acetate, water insoluble.
2, ph stability test
The stability of object: test compounds T to acid-base condition.
Principle: if compound T decomposes under Acidity of Aikalinity condition, can observe a plurality of speckles when thin plate launches.
Method: 6mg sample is dissolved in 1200 μ l acetone, adds 400 μ l water mix homogeneously to be made into sample liquid.According to temperature and Acidity of Aikalinity, be divided into 6 groups, i.e. room temperature acid, alkali, matched group and 60 ℃ of acid, alkali, matched group, every group adds 200
μ l sample liquid and 400 μ l acetone.Acid constituents does not add 200 μ l1N hydrochloric acid, and alkaline constituents does not add 200 μ l20%NaOH solution, and matched group adds respectively 200 μ l water.Room temperature acid, alkali, matched group are placed in room temperature (25 ℃) lower 1 hour, and 60 ℃ of acid, alkali, matched groups are placed in lower 1 hour of 60 ℃ of water-baths, and some plate launches with 40: 1 methylene chloride-methanol systems.
Result: from a plate development situation, compare with room temperature matched group, room temperature acid group and room temperature alkali group have obvious decomposition speckle at initial point place; Compare with 60 ℃ of matched groups, 60 ℃ of acid groups and 60 ℃ of alkali groups have obvious decomposition speckle at initial point place.
Conclusion: compound T is all unstable to strong acid, highly basic under room temperature and 60 ℃ of conditions.
The pharmacodynamic evaluation of bis-: two kinds of CD38 enzyme inhibitors of embodiment in airway of mice high response disease model
Experiment material: 30g left and right bull kunming mice (clean level), is purchased from Department Of Medicine, Peking University's Experimental Animal Center; AniRes2005 animal lung function analytical system (Beijing Bei Lanbo Science and Technology Ltd.); Methacholine (MCH, U.S. Sigma company); Malonaldehyde (MDA) test kit (Bioengineering Research Institute is built up in Nanjing); Compound H [3-carbamoyl-1-((2-(3-phenoxy-phenoxy) ethyoxyl) methyl) pyridine]; Compound T[5-(3-phenyl propionamido) N-(4-carbethoxy phenyl)-1H-3-indole carboxamides].
Experimental technique:
1, buy approximately 68 of 30g left and right bull KM mices, modeling is weighed the previous day, remove underweight or overweight mice, only retain 60, be divided at random 6 groups: Normal group, model group, hormone group, Meptin group, compound H treatment group and compound T treatment group; Except Normal group, each group needs ozone modeling, and method is ozone attack every afternoon 10min, continuous 5 days, within the 6th day, surveys data, sampling this (experiment front and back take Mouse Weight, calculate body weight change); Dosage regimen: Normal group and model group contain the emulsifying agent of sodium carboxymethyl cellulose (0.5%) and vegetable oil (6%); Hormone group is the emulsifying agent containing 0.1mg/ml hormone, and procaterol group is the emulsifying agent containing 7.5ug/ml procaterol; Compound H treatment group and compound T treatment group are respectively 5mg/ml, the emulsifying agent of 6mg/ml; Every morning, administration in evening, every mice gives 0.2ml at every turn, continuous 5 days; Append gavage once the 6th day morning.
2, the 6th day with 1% pentobarbital sodium anesthetized mice, uses AniRes2005 animal lung function analytical system to measure airway of mice function, and the Concentraton gradient that used tool medicine is pre-cooling is 120ug/ml, 240ug/ml, 480ug/ml, 960ug/ml, the methacholine of 1.92mg/ml; Measure complete, by the ligation of mice left pulmonary main bronchus, right lung reclaims broncho-pulmonary irrigating solution (BALF), then clip left pulmonary with PBS lavation, every group of front 5 use, 4% paraformaldehyde preserved (for lung pathology merit sheet), preserves for latter 5 in-80 degree refrigerator freezings; In mouse orbit, get blood, (for blood middle leukocytes, red blood cell count(RBC)) preserved in anticoagulant.
3, BALF is centrifugal under 1500r/min*5min condition, precipitation is for numeration of leukocyte, and supernatant is used for measuring malonaldehyde (MDA).
Result and discussion:
1, with regard in before and after experiment 5 days, Mouse Weight changes, compare with Normal group, model group Mouse Weight obviously alleviates; Other each group is compared with model group, and hormone group Mouse Weight alleviates more obvious, and comprises that the Mouse Weight of respectively organizing of T compound group changes and to compare and there is no statistical significance with model group.Illustrate that ozone modeling causes that Mouse Weight reduces, the hormone therapy of this concentration can further reduce Mouse Weight in the situation that of ozone modeling, has overt toxicity, and comprises that the other medicines of T compounds for treating do not find this general toxicity.
2, from blood middle leukocytes and red blood cell count(RBC), between each group, more all there is no statistical significance, but compare with Normal group, hormone group has the trend (P value is respectively 0.087 and 0.067) that reduces blood middle leukocytes and erythrocyte number, the hormone therapy that this concentration is described has certain hematotoxicity, and comprises that the other medicines of T compounds for treating do not find hematotoxicity.
3, the leukocyte count of analyzing broncho-pulmonary irrigating solution (BALF), as shown in Figure 2, ozone modeling can obviously increase leukocyte count in BALF to result, illustrates that ozone modeling has caused that mice trachea reacts with lung local inflammation; Other each group is compared with model group, in hormone group and H compound group BALF, quantity of leucocyte obviously reduces, the quantity of leucocyte of Meptin group and T compound group has the trend (P value is respectively 0.090 and 0.068) of reduction, illustrate that hormone and H compounds for treating can obviously alleviate the mice trachea that ozone modeling causes and react with lung local inflammation, Meptin can to a certain degree alleviate ozone modeling with T compounds for treating and cause that mice trachea reacts with lung local inflammation.
4, malonaldehyde (MDA) content of analyzing broncho-pulmonary irrigating solution (BALF), as shown in Figure 3, ozone modeling can obviously increase the MDA content in BALF to result; Other each group is compared with model group, and the MDA content in hormone group, Meptin group and T compound group BALF obviously reduces, and the MDA content of H compound group and model group is without significant difference.MDA is the catabolite of polyunsaturated fatty acid peroxide, body produces oxygen-derived free radicals by enzyme system and non-enzyme system, the polyunsaturated fatty acid that the latter can attack in biomembrane causes lipid peroxidation, and form thus lipid peroxide, make histiocyte damaged, MDA is an important oxidative damage parameters.Therefore, ozone modeling has caused mice trachea and lung selective oxidation damage, and hormone, Meptin and T compounds for treating can obviously alleviate mice trachea and the lung selective oxidation damage that ozone modeling causes, and H compounds for treating is without this pharmacological action.
5, record every mice airway resistance (RL) value of (base state, the methacholine excited state of 120ug/ml, 240ug/ml, 480ug/ml, 960ug/ml and 1.92mg/ml) under six kinds of different conditions and (be made as respectively X
0, X
1, X
2, X
3, X
4with X
5), then establishing every airway resistance under mice base state is 1, the airway resistance value under base state divided by this mice respectively of the airway resistance value under four kinds of variable concentrations Mch excited states, obtains five relative value and (is X
1/ X
0, X
2/ X
0, X
3/ X
0, X
4/ X
0and X
5/ X
0), be RL ratio; Then ask the meansigma methods of respectively organizing RL ratio under the corresponding six kinds of states of mice; Then take these six kinds of states is abscissa, and the meansigma methods of the RL ratio of airway resistance is vertical coordinate, standardized continuous curve of every group of mice, then compare the rising trend of these curves, rising amplitude is larger, represents that mice is more obvious to the reaction of Mch, and airway reactivity is higher.Result is as shown in table 1, compare with Normal group, model group presents airway hyperreactivity significantly, other each group and model group comparison, Meptin group and the airway resistance of T compound group obviously reduce, and hormone group and the airway resistance of H compound group are totally close to model group.Illustrating that T compound has with Meptin reduces the effect that ozone is attacked the airway hyperreactivity cause similarly, and hormone and H compounds for treating are without obvious effect.
Table 1: each organizes the RL ratio of mice under different excited states
* P < 0.05 vs Normal group # P < 0.05 vs model group
6, record equally the dynamic lung compliance value (Cdyn) of every mice under six kinds of different conditions, calculate five relative value, be Cdyn ratio; Then ask equally the meansigma methods of respectively organizing Cdyn ratio under the corresponding six kinds of states of mice; Then take these six kinds of states is abscissa, and the meansigma methods of the Cdyn ratio of airway resistance is vertical coordinate, standardized continuous curve of every group of mice, then the relatively downward trend of these curves, fall is larger, represents that mice is more obvious to the reaction of Mch, and airway reactivity is higher.Result is as shown in table 2, compare with Normal group, the Cdyn ratio of model group mice obviously reduces, other each group and model group comparison, Meptin group and T compound group dynamic lung compliance obviously increase, and hormone group and the airway resistance of H compound group are totally close to model group.This result is again proved T compound and is had with Meptin and reduce similarly the effect that ozone is attacked the airway hyperreactivity cause, and hormone and H compounds for treating are without obvious effect.
Table 2: each organizes the Cdyn ratio of mice under different excited states
* P < 0.05 vs Normal group # P < 0.05 vs model group
7, observe and respectively to organize the HE dyeing of the dirty pathological section of mouse lung (observation index comprises epithelial cell shedding, tube wall thickens, tube wall smooth muscle layer thickens, tube chamber endocrine amount, peripheral vessels and bronchitis cell ooze out degree and alveolar structure changes degree), result is if Fig. 4 (* 100 times) is with as shown in Fig. 5 (* 400 times), the lung tissue lesion degree of model group is larger than Normal group, other each group and model group comparison, the lung lesion degree of finding Meptin group and T compound group is significantly less than model group, and though the lung lesion degree of hormone group and H compound group has than model group and to a certain degree alleviates, but not obvious.Show that ozone attack can cause the airway epithelia of mice and alveolar structure to change, peripheral vessels and bronchitis cell ooze out; Meptin and T compounds for treating can alleviate ozone and attack air flue and the alveolar pathological change causing, and hormone and H compounds for treating DeGrain.
In sum, T compounds for treating can alleviate ozone and attack institute's air flue that causes and alveolar pathological change, inflammatory reaction, oxidative damage and airway hyper-reaction, and without the obvious hematotoxicity of nothing and general toxic and side effects.Illustrate that T compound is worth larger as the exploitation of potential treatment airway hyperreactivity disease new drug.
Claims (3)
1. a medicine that is used for the treatment of airway hyperreactivity disease, Chinese name: 5-(3-phenyl propionamido)-N-(4-carbethoxy phenyl)-1H-3-indole carboxamides; Classification: 5-replaces propionamido-N-substituted-phenyl-1H-3-indole carboxamides class.
2. according to the medicine of the treatment airway hyperreactivity disease described in right 1, it is characterized in that a kind of CD38 enzyme inhibitor.
3. by compound claimed in claim 1, it is characterized in that this compound is non-covalent class inhibitor, the indole heterocyclic micromolecular inhibitor of CD38.
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| CN101301403A (en) * | 2008-07-08 | 2008-11-12 | 中南大学 | Clerodendrum bungei extract and use thereof for treating airway hyperreactivity |
| WO2012004554A1 (en) * | 2010-07-06 | 2012-01-12 | St George's Hospital Medical School | Aldehyde compounds as inhibitors of dust mite group 1 peptidase allergen and their use |
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| WO2012004554A1 (en) * | 2010-07-06 | 2012-01-12 | St George's Hospital Medical School | Aldehyde compounds as inhibitors of dust mite group 1 peptidase allergen and their use |
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| SHUANG ZHANG ET AL.: "Comparative Analysis of Pharmacophore Features and Quantitative Structure–Activity Relationships for CD38 Covalent and Non-covalent Inhibitors", 《CHEM BIOL DRUG DES》 * |
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