CN103655557B - Purposes of the CD38 enzyme inhibitors in airway hyperreactivity disease is treated - Google Patents
Purposes of the CD38 enzyme inhibitors in airway hyperreactivity disease is treated Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of medicine for treating airway hyperreactivity disease, the indole carboxamides of 5 (3 phenylpropionyl amino) N (4 carbethoxy phenyl) 1H 3.The medicine is a kind of CD38 enzyme inhibitors, can be by suppressing Ca2+Discharge diastole bronchus smooth muscle, symptomatic treatment airway hyperreactivity disease；We make the high reaction model of airway of mice using ozone, while give the emulsifying agent gavage treatment of the medicine, it is found that the airway of mice resistance through the drug therapy substantially reduces, dynamic lung compliance substantially increases, lung lesion degree mitigates；In addition, experiment finds that the medicine also has anti-inflammatory, antioxidation, obvious toxic-side effects are not found, and there is Development volue well, belong to drug field.
Description
Technical field：
The present invention relates to a kind of medicine for treating airway hyperreactivity disease, 5- (3- phenylpropionyls amino)-N- (4- ethoxies
Carbonyl phenyl) -1H-3- indole carboxamides.The medicine is a kind of CD38 enzyme inhibitors, is mainly reached by expanding tracheal smooth muscles
Therapeutic purposes, while there is anti-inflammatory, antioxidation, belong to drug field.
Background technology：
Airway hyperreactivity refers to trachea-bronchial epithelial cell in itself to various stimulations, including specific antigen stimulates and non-specific
Sexual stimulus, such as physics, chemical stimulation, overreaction is presented, is the key character that branchial asthma patients are different from normal person[1]。
Although the risk factor of airway hyper-reaction is varied, and the therapeutic action link of various medicines is different, and new treatment is ground
It is also in multidirectional to study carefully, but substantially from anti-inflammatory, antihistamine, allergic reaction medium sustained-release agent, corresponding suit the medicine to the illness[2]And traditional Chinese medicine
Treatment[3]Set out.At present, large and small mouse model of the researcher using more airway hyper-reaction model for egg protein (OVA) sensitization,
But the weak point of the modeling method is that the modeling time is long, success rate is not high and complex operation.Due to industry and automobile exhaust gas
Influence, agricultural area, surface ozone can be formed and assembled especially around big city.Surface ozone is to human body, especially to eye
Eyeball, respiratory tract etc. have erosion and detrimental effect.There are infringement and environment of the Many researchers from ozone to people and animal to protect both at home and abroad
Corner protector degree is studied ozone, it is found that ozone can not only aggravate respiratory disease, it was found that smelly in air pollutants
Oxygen is directly related with asthma attack[4-7].Early in 2001, just there was rabbit branch gas of the researcher using ozone attack original cuiture the country
Pipe epithelial cell, observe the antioxidation activity of bronchial epithelial cell[8].Zhang Jiansong of Hunan Normal University etc.[9]Utilize ozone
The high reaction model of rat airway is made, and compared with the rat model of egg protein (OVA) sensitization, it is found that ozone suction prepares non-change
The method of different in nature airway hyperreactivity rat model is simple and feasible.Seminar's current research is found through dexamethasone in treatment
Afterwards, the rat airway mucous secretion of ozone modeling significantly reduces, airway epithelia mucus lays in index and goblet cell metaplasia index
It is decreased significantly[10].CD38 developed by molecule and distribution quite it is extensive, main expression is in jejune hematopoietic cell and the leaching of activation
Bar like cell, also has expression in skeletal muscle, cardiac muscle, airway smooth muscle and uterine smooth muscle CD38 molecules.Pass through CD38 molecules
The cADPR (cyclic adenosine diphosphate ribose, cADPR) of enzyme catalysis generation comes
Adjust intracellular Ca2+Release and adjust cellular contraction[11-13].The contractility of airway smooth muscle relies primarily on thin in smooth muscle
Intracellular Ca2+Concentration, CD38 molecules can adjust intracellular Ca2+Concentration so that influence airway smooth muscle contraction, in asthma
Pathogenesis in play critically important effect[14].Inventor has synthesized two kinds of CD38 enzyme inhibitors, makes emulsifying agent, gavage
Airway hyper-reaction mouse model caused by ozone is treated, pharmaceutical research is carried out, completes the present invention.
● [1] Qin XQ, Xiang Y, Liu C, et al.The role of bronchial epithelial
Cells in airway hyperresponsiveness.Acta Physiologica Sinica, 2007,59 (4)：454-
464.
●[2]Marone G.Asthma：Recent advances.Immunol Today, 1998,19 (1)：5-9.
● the refined Chinese medicines of [3] Zeng Rong, Huang Ren are relievingd asthma the progress china medical abstract clinical practice of mechanism, and 2005,26
(6)：736-739.
● [4] Schelegle ES, Walby WF.Vagal afferents contribute to exacerbated
airway responses following ozone and allergen challenge.Respir Physiol
Neurobiol.2012,181 (3)：277-85.
● [5] Kesic MJ, Meyer M, Bauer R, Jaspers I.Exposure to ozone modulates
human airway protease/antiprotease balance contributing to increased
Influenza A infection.PLoS One.2012,7 (4)：e35108.
● [6] Sheffield PE, Knowlton K, Carr JL, Kinney PL.Modeling of regional
climate change effects on ground-level ozone and childhood asthma.Am J Prev
Med.2011,41 (3)：251-7.
● [7] Glad JA, Brink LL, Talbott EO, Lee PC, Xu X, Saul M, Rager J.The
relationship of ambient ozone and PM(2.5)levels and asthma emergency
department visits：possible influence of gender and ethnicity.Arch Environ
Occup Health.2012,67 (2)：103-8.
● [8] Qin Xiaoqun, on the sunny side, pipe tea perfume, wait integrins association reaction to raise rabbit bronchial epithelial cell antioxygen
Change ability [J] Journals of physiology, 2001,53 (1)：41-44.
● [9] Li Xiang, Wang Xiaomei, Zhang Jiansong.The foundation of two kinds of airway hyper-reaction rat models Hunan compared with is pedagogical big
Learn journal (medicine), 2009,6 (1)：17-22
● [10] Kumamoto is strong, Li Xiang, Li Xibing, Chen Qiuxia, Zhang Jiansong, and aquaporin 1 glues to airway hyper-reaction rat
The influence of liquid hypersecretion.Hunan Normal University's journal (medicine), 2012,9 (1)：6-10
● [11] Dogan S, Deshpande DA, Kannan MS.Changes in CD38expression and
ADP-ribosyl cyclase activity in rat myometrium during Pregnancy：influence of
Sex steroid hormones.Biol Reprod, 2004,71 (1) 97-103.
● [12] Deshpande DA, Dogan S, Walseth TF, et al.Modulation of calcium
signaling by interleakin IL-13in human airway smooth muscle：role of CD38/
Eyclic adenosine diphosphate ribose pathway.Am J Respir Cell Mol Bio, 2004,31
(1)：36-42.
● [13] Takahashi J, KagayaY, Kato I, et al.Deficit of CD38/cyclic ADP-
ribose is differentially compensated in hearts by gender.Biochem Biophys Res
Commun.2003,312 (2)：434-440.
● [14] Deshpande DA, White TA, Dogan S, et al.CD38/cyclic ADP-ribose
signaling：role in the regulation of calcium homeostasis in airway smooth
Muscle.Am J Physiol Lung Cell Mol Physiol, 2005,288 (5)：L773-788.
The content of the invention：
The present invention seeks to study two kinds of CD38 enzyme inhibitors [3- carbamoyls -1- ((2- (3- phenoxy-phenoxies)
Ethyoxyl) methyl) pyridine and 5- (3- phenylpropionyls amino)-N- (4- carbethoxy phenyls) -1H-3- indole carboxamides], it is used for
Treat airway hyperreactivity disease.
Inventor is based on known CD38 crystal structures, using the strategy of step-sizing to commercial small molecule database
(Sigma and Maybridge) has carried out virtual screening.Obtained compound is taking into full account the reasonability and structure of binding pattern
On the basis of multifarious, wherein 23 compounds are bought, have carried out the test of CD38NADase inhibitory activity.According to active testing
As a result and structure novelty, synthesis difficulty, can be derivative etc. factor, select primer.By to the multiple of primer structure
Transformation and active testing, finally give two kinds of CD38 enzyme inhibitors.
Inventor has found that 5- (3- phenylpropionyls amino)-N- (4- carbethoxy phenyls) -1H-3- indoles first
Acid amides by suppressing CD38 enzymatic activitys except outside expanding tracheal smooth muscles symptomatic treatment airway hyperreactivity disease, can also have
There are anti-inflammatory, antioxidation activity.Among the present invention, by using the high reaction model of airway of mice of ozone making, inventor grinds
Study carefully the pharmacological action of both CD38 enzyme inhibitors, find a kind of compound 5- (3- phenylpropionyls amino)-N- (4- therein
Carbethoxy phenyl) -1H-3- indole carboxamides can substantially reduce airway of mice resistance, increase dynamic lung compliance, mitigate lung
Lesion degree；In addition, experiment finds that the medicine also has anti-inflammatory, antioxidation, obvious toxic-side effects are not found.
Medicine of the present invention is yellowish white powder, 192-194 DEG C of fusing point, is dissolved in DMF, acetone, is slightly soluble in methanol, dichloromethane
Alkane, it is not soluble in water, decomposed in the presence of strong acid, highly basic.Medicine of the present invention can also contain clinically applicable pharmaceutical excipient.
Its formulation can apply to the various regular dosage forms of clinic, such as pill, tablet, powder, oral liquid, injection
Deng.
Brief description of the drawings：
Fig. 1：Compound T structural formula；
Fig. 2：Leukocyte count in BALF；
* the VS model groups of 0.05 vs Normal group # P ＜ of P ＜ 0.05
P=0.090 VS model group P=0.068 VS model groups (n=9~10)
Fig. 3：MDA contents in BALF；
* the VS model groups (n=9~10) of 0.01 vs Normal group # P ＜ of P ＜ 0.01
Fig. 4：The HE colored graphs (× 100 times) of each group mouse lung pathological section；
Fig. 5：The HE colored graphs (× 400 times) of each group mouse lung pathological section.
Embodiment：
Embodiment one：Compound T [5- (3- phenylpropionyls amino)-N- (4- carbethoxy phenyls) -1H-3- indoles formyls
Amine] physicochemical property
Compound T structural formula is as shown in figure 1, molecular weight is 455.51, yellowish white powder, and 192-194 DEG C of fusing point is molten
In DMF, acetone, methanol, dichloromethane are slightly soluble in, it is not soluble in water, decomposed in the presence of strong acid, highly basic.Its solubility and soda acid
Stability can be proved by following experiment.
1st, solubility test
Purpose：Dissolubilities of the test compound T in different solvents
Principle：When 20 DEG C, the amount of the solvent of the dissolving in 100g solvents is that 1~10g is solvable, and 0.01g-1g is micro-
Molten, below 0.01g is indissoluble.A certain amount of solvent is added into quantitative sample, observes dissolving situation.
Method：2mg samples are taken, add solvent concussion, clear is considered as without solid to be completely dissolved.
Slightly soluble is that can 2mg samples be dissolved in 200mg solvents with solvable line of demarcation, insoluble to divide into 2mg with sl. sol.
Can sample be dissolved in less than in 20g solvents.Therefore, 200mg, 2g, 20g solvent are added from small to large into 2mg samples until molten
Solution, dissolving situation is observed, record the dissolving section of sample.
As a result：Dissolving situation of the 2mg samples in 200mg methanol be：It can not be completely dissolved；2mg samples are in 200mg methanol
In dissolving situation be：It is completely dissolved；Dissolving situation of the 2mg samples in 200mg dichloromethane be：It can not be completely dissolved；2mg
Dissolving situation of the sample in 2g dichloromethane be：It is completely dissolved；Dissolving situation of the 2mg samples in 200mg acetone be：Completely
Dissolving；Dissolving situation of the 2mg samples in 200mg ethyl acetate be：It can not be completely dissolved；2mg samples are in 2g ethyl acetate
Dissolving situation be：It is completely dissolved；Dissolving situation of the 2mg samples in 200mg DMFs be：It is completely dissolved；
Dissolving situation of the 2mg samples in 20g water be：Endless fully dissolved.
Conclusion：Compound T is dissolved in DMF, acetone, is slightly soluble in methanol, dichloromethane, ethyl acetate, no
It is dissolved in water.
2nd, ph stability is tested
Purpose：Stability of the test compound T to acid-base condition.
Principle：If compound T is decomposed under the conditions of acid-base property, thin plate is observed that multiple spots when deploying.
Method：6mg samples are dissolved in 1200 μ l acetone, 400 μ l water of addition are well mixed to be made into sample liquid.According to temperature and
Acid-base property, it is divided into 6 groups, i.e. room temperature acid, alkali, control group and 60 DEG C of acid, alkali, control groups, every group of addition 200
μ l sample liquids and 400 μ l acetone.Acid constituents does not add 200 μ l1N hydrochloric acid, and it is molten that alkaline constituents does not add 200 μ l20%NaOH
Liquid, control group are then separately added into 200 μ l water.Room temperature acid, alkali, control group are placed in room temperature (25 DEG C) lower 1 hour, 60 DEG C of acid, alkali, right
It is placed according to group in 60 DEG C of water-baths lower 1 hour, puts plate, is deployed with 40: 1 methylene chloride-methanol systems.
As a result：From the point of view of a plate expansion situation, compared with room temperature control group, room temperature acid group and room temperature alkali group at the origin have
It is obvious to decompose spot；Compared with 60 DEG C of control groups, 60 DEG C of acid groups and 60 DEG C of alkali group at the origins have obvious decomposition spot.
Conclusion：Compound T is unstable to strong acid, highly basic under the conditions of room temperature is with 60 DEG C.
Embodiment two：Pharmacodynamic evaluation of two kinds of CD38 enzyme inhibitors in airway of mice high response disease model
Experiment material：30g or so bulls kunming mice (cleaning grade), is purchased from Department Of Medicine, Peking University experimental animal
The heart；AniRes2005 animal lung functions analysis system (Beijing Bei Lanbo Science and Technology Ltd.s)；Methacholine (MCH, the U.S.
Sigma companies)；MDA (MDA) kit (Bioengineering Research Institute is built up in Nanjing)；Compound H [3- carbamoyls -1-
((2- (3- phenoxy-phenoxies) ethyoxyl) methyl) pyridine]；Compound T [5- (3- phenylpropionyls amino) N- (4- carbethoxyl groups
Phenyl) -1H-3- indole carboxamides].
Experimental method：
1st, 30g or so bull KM mouse about 68 are bought, modeling the previous day weighs, and removes underweight or overweight small
Mouse, only retain 60, be randomly divided into 6 groups：Normal group, model group, hormone group, Meptin group, compound H treatment groups are with changing
Compound T treatment groups；In addition to Normal group, each group needs ozone modeling, method be every afternoon ozone attack 10min, continuous 5
My god, survey within the 6th day data, sampling this (mouse weight being weighed before and after experiment, calculate changes of weight)；Dosage regimen：Normal group
The emulsifying agent containing sodium carboxymethylcellulose (0.5%) Yu vegetable oil (6%) is given with model group；Hormone group is to swash containing 0.1mg/ml
The emulsifying agent of element, Procaterol group are the emulsifying agent of the Procaterol containing 7.5ug/ml；Compound H treatment groups treat with compound T
Group respectively 5mg/ml, 6mg/ml emulsifying agent；Every morning, it is administered at night, every mouse gives 0.2ml every time, and continuous 5
My god；6th day morning added gavage once.
2nd, the 6th day with 1% yellow Jackets anesthetized mice, uses AniRes2005 animal lung functions analysis system to measure
Airway of mice function, used tool medicine are that the concentration gradient of precooling is 120ug/ml, 240ug/ml, 480ug/ml, 960ug/ml,
1.92mg/ml methacholine；Measurement is finished, and mouse left pulmonary main bronchus is ligatured, and right lung reclaims branch with PBS lavations
Tracheae lung-douching fluid (BALF), then clip left pulmonary, 5 paraformaldehydes of use 4% preserve (being used for lung pathology work(piece) before every group,
5 preserve in -80 degree refrigerator freezings afterwards；Blood is taken in mouse orbit, anti-freezing is preserved (based on blood middle leukocytes, red blood cell
Number).
3rd, BALF is centrifuged under the conditions of 1500r/min*5min, precipitated for white blood cell count(WBC), supernatant is used to measure
MDA (MDA).
As a result with discussion：
1st, for mouse weight changes in 5 days before and after experiment, compared with Normal group, model group mouse weight is obvious
Mitigate；For other each groups compared with model group, the mitigation of hormone group mouse weight is more obvious, and each including T compound groups
Group mouse weight change is not statistically significant compared with model group.Illustrate that ozone modeling causes mouse weight to reduce, the concentration
Hormone therapy mouse weight can be further reduced in the case of ozone modeling, there is overt toxicity, and control including T compounds
Other medicines including treatment do not find this general toxicity.
2nd, from the point of view of blood middle leukocytes and red blood cell count(RBC), be more not statistically significant between each group, but with just
Normal control group is compared, hormone group have reduce blood middle leukocytes and erythrocyte number trend (P values be respectively 0.087 and
0.067), illustrating the hormone therapy of the concentration has certain hematotoxicity, and the other medicines including T compounds for treating are not
It was found that hematotoxicity.
3rd, the leukocyte count of bronchoalveolar lavage fluid (BALF) is analyzed, as a result as shown in Fig. 2 ozone modeling can substantially increase
Leukocyte count in BALF, illustrate that ozone modeling causes mouse tracheae and lung local inflammation reaction；Other each groups and model group phase
Than hormone group substantially reduces with quantity of leucocyte in H compound groups BALF, the quantity of leucocyte of Meptin group and T compound groups
There is the trend (P values are respectively 0.090 and 0.068) of reduction, illustrate that hormone and H compounds for treating can substantially mitigate ozone modeling and draw
The mouse tracheae risen and lung local inflammation reaction, Meptin can mitigate ozone modeling to a certain degree with T compounds for treating and cause
Mouse tracheae and lung local inflammation reaction.
4th, MDA (MDA) content of bronchoalveolar lavage fluid (BALF) is analyzed, as a result as shown in figure 3, ozone modeling energy
MDA contents in obvious increase BALF；Other each groups are compared with model group, in hormone group, Meptin group and T compound groups BALF
MDA contents substantially reduce, the MDA contents of H compound groups and model group are without significant difference.MDA is polyunsaturated fatty acid mistake
The catabolite of oxide, body produce oxygen radical by enzyme system and non-enzyme system, and the latter can attack more in biomembrane
Unrighted acid triggers lipid peroxidation, and is consequently formed MDA, is damaged histocyte, MDA is
One important oxidative damage parameters.Therefore, ozone modeling causes mouse tracheae and damaged with lung selective oxidation, hormone, Mei Pu
Mouse tracheae caused by ozone modeling can substantially be mitigated with T compounds for treating clearly to damage with lung selective oxidation, and H compounds for treating
Without this pharmacological action.
5th, measure every mouse under six kinds of different conditions (base state, 120ug/ml, 240ug/ml, 480ug/ml,
960ug/ml and 1.92mg/ml methacholine excited state) airway resistance (RL) value (be set to X0、X1、X2、X3, X4
With X5), the airway resistance under every mouse base state is then set as 1, the air flue under four kinds of various concentrations Mch excited states
The airway resistance value of Resistance Value difference divided by this mouse under base state, it (is X to obtain five relative values1/X0、X2/X0、X3/
X0、X4/X0And X5/X0), as RL ratios；Then the average value of RL ratios under the corresponding six kinds of states of each group mouse is sought；Then with this
Six kinds of states are abscissa, and the average value of the RL ratios of airway resistance is ordinate, every group of continuous curve of the standardized bar of mouse, so
Compare the rise trend of these curves afterwards, elevation amplitude is bigger, represents that reaction of the mouse to Mch is more obvious, airway reactivity is got over
It is high.As a result as shown in table 1, compared with Normal group, significantly airway hyperreactivity, other each groups and model is presented in model group
Group compares, and Meptin group substantially reduces with T compound groups airway resistance, and hormone group totally connects with H compound groups airway resistance
It is bordering on model group.Illustrate that T compounds have the work that the airway hyperreactivity caused by ozone attack is similarly reduced with Meptin
With, and hormone and H compounds for treating are without obvious effect.
Table 1：RL ratio of each group mouse under different excited states
* the vs model groups of 0.05 vs Normal group # P ＜ of P ＜ 0.05
6th, dynamic lung compliance value (Cdyn) of the every mouse under six kinds of different conditions is equally measured, calculates five relatively
Value, as Cdyn ratios；Then the average value of Cdyn ratios under the corresponding six kinds of states of each group mouse is equally sought；Then with this six kinds
State is abscissa, and the average value of the Cdyn ratios of airway resistance is ordinate, every group of continuous curve of the standardized bar of mouse, then
Compare the downward trend of these curves, fall is bigger, represents that reaction of the mouse to Mch is more obvious, airway reactivity is higher.
As a result as shown in table 2, compared with Normal group, the Cdyn ratios of model group mouse substantially reduce, other each groups and model group
Compare, Meptin group substantially increases with T compound groups dynamic lung compliance, and hormone group is overall with H compound groups airway resistance
Close to model group.This result proves T compounds again has the gas similarly reduced with Meptin caused by ozone attack
The effect of road high response, and hormone and H compounds for treating are without obvious effect.
Table 2：Cdyn ratio of each group mouse under different excited states
* the vs model groups of 0.05 vs Normal group # P ＜ of P ＜ 0.05
7th, observe each group mouse lung pathological section HE dyeing (observation index include epithelial cell shedding, tube wall thickening,
Tube wall smooth muscle layer thickens, tube chamber endocrine object amount, peripheral vessels and bronchitis cell oozes out degree and alveolar structure changes
Change degree), as a result as shown in Fig. 4 (× 100 times) and Fig. 5 (× 400 times), the various pulmonary lesions degree of model group compares normal control
Group is big, and other each groups find that the lung lesion degree of Meptin group and T compound groups is significantly less than model group compared with model group,
And though the lung lesion degree of hormone group and H compound groups has than model group and mitigated to a certain degree, unobvious.Show that ozone is attacked
The airway epithelia and alveolar structure that can result in mouse change, and peripheral vessels and bronchitis cell ooze out；Meptin and Tization
Compound treatment can mitigate the air flue and alveolar pathological change caused by ozone attack, and hormone and H compounds for treating effect are not
Substantially.
In summary, air flue and alveolar pathological change, inflammation are anti-caused by T compounds for treating can mitigate ozone attack
Should, oxidative damage and airway hyper-reaction, and without without obvious hematotoxicity and systemic toxic side effect.Illustrate T compounds as latent
Treatment airway hyperreactivity disease new drug Development volue it is larger.
Claims (3)
1. a kind of medicine for being used to treat airway hyperreactivity disease, Chinese name：5- (3- phenylpropionyls amino)-N- (4- ethoxies
Carbonyl phenyl) -1H-3- indole carboxamides.
2. according to the medicine of the treatment airway hyperreactivity disease described in claim 1, it is characterized in that a kind of CD38 enzyme inhibitors.
3. according to a kind of medicine described in claim 1, it is characterised in that the medicine is CD38 non-covalent class inhibitor, indoles
Heterocycle type small molecular inhibitor.
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Citations (2)
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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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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (3)
| Title |
|---|
| Comparative Analysis of Pharmacophore Features and Quantitative Structure–Activity Relationships for CD38 Covalent and Non-covalent Inhibitors;Shuang Zhang et al.;《Chem Biol Drug Des》;20151231(第86期);第1411-1424页 * |
| Treatment Responses of Procaterol and CD38 Inhibitors in an OzoneInduced Airway Hyperresponsiveness Mice Model;Zheng Deng et al.;《Biol. Pharm. Bull.》;20131231;第36卷(第8期);第1348-1355页 * |
| 一种新合成化合物对臭氧诱导气道高反应小鼠肺部损伤的保护作用;邓政等;《中国新药杂志》;20141231;第23卷(第9期);第1004-1011页 * |
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