CN101474174B - Application of N-[2-methyl-1-(pyrrolidine-1-carbonyl)-propyl]-3-phenyl propionamide in pharmacy - Google Patents
Application of N-[2-methyl-1-(pyrrolidine-1-carbonyl)-propyl]-3-phenyl propionamide in pharmacy Download PDFInfo
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- CN101474174B CN101474174B CN2009100284816A CN200910028481A CN101474174B CN 101474174 B CN101474174 B CN 101474174B CN 2009100284816 A CN2009100284816 A CN 2009100284816A CN 200910028481 A CN200910028481 A CN 200910028481A CN 101474174 B CN101474174 B CN 101474174B
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Abstract
The invention relates to an application of N-(2-methyl-1-(pyrrolidine-1-carbonyl)-propyl)-3-phenyl propanamide (AS-1) in pharmaceuticals for preventing and treating ventricular remodeling and cardiac failure, application of N-(2-methyl-1-(pyrrolidine-1-carbonyl)-propyl)-3-phenyl propanamide (AS-1) in pharmaceuticals for preventing and treating myocardial hypertrophy and ventricular remodeling resulting from pressure load, and application of N-(2-methyl-1-(pyrrolidine-1-carbonyl)-propyl)-3-phenyl propanamide (AS-1) in pharmaceuticals for preventing and treating acute ischemic heart disease and cardiac ischemia-reperfusion injury.
Description
One, technical field
The present invention relates to micromolecular compound N-[2-methyl isophthalic acid-(pyrrolidine-1-the carbonic acyl radical)-propyl group of chemosynthesis]-(hydrocinnamoyl-L-valyl pyrrolidine, purposes AS-1) relate in particular to the application in pharmaceutical field to the 3-Phenylpropionamide.
Two, background technology
Since nineteen nineties, cardiovascular disease M ﹠ M worldwide obviously increases, and heart failure has become the primary cause of disease that causes death.Heart failure (heart failure) is meant the contraction and/or the diastolic function generation obstacle of heart under the effect of various paathogenic factors, make the absolute or decline relatively of cardiac output, be that cardiac pump function weakens, so that can not satisfy the pathophysiological process or the syndrome of organism metabolism.The commonly encountered diseases that hypertension, myocardial infarction, aortic valve are narrow, myocarditis etc. is heart failure because of.The basis that heart failure takes place is that (Ventricular Remodeling, VR), reverse remodeling ventricle is the key of heart failure therapy to remodeling ventricle.
Cardiac hypertrophy and to reinvent be cardiac function by normal to depleted transition process, also be in the heart tissue a large amount of protein expressions unusually, the process that changes of cardiac shape structure.In this process, variously cause cardiac hypertrophy and reinvent factor (as the heart overload etc.) changes relevant nuclear factor by signal transduction pathway in the heart cell activity, cause the expression of a large amount of genes matter in the heart tissue to occur making the morphosis of heart and function change unusually.
Chang Yong heart failure resistance medicine comprises clinically: diuretic, positive inotropic medicament such as Folium Digitalis Purpureae class, hypertensin enzymeinhibitor, beta-blocker, medicament for expanding vascellum etc.Though these medicines can be alleviated the symptom of heart failure, late result is unsatisfactory.
The recent nuclear factor κ B (NF-κ B), mitogen activated protein kinase (MAPK) signal path of discovering brought into play important regulation in the developing of remodeling ventricle.This signal path up-regulated in myocardial hypertrophy or ischemic cardiomyopathy, the activation of inhibition or reticent this signal path can obviously improve the symptom of myocardial hypertrophy or ischemic cardiomyopathy, reduces the infiltration of inflammatory cell.
People such as Tamas Bartfai discover a kind of micromolecular compound N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-3-Phenylpropionamide (AS-1) can suppress the activation of nuclear factor κ B (NF-κ B), mitogen activated protein kinase (MAPK) signal path.This chemical compound can suppress the activation of the beta induced MAPK signal path of IL-1 in EL4 mouse thymus oncocyte and mouse lymphocyte.In addition, people's such as Christopher N.Davis discovers that at the hypothalamus neurons cell AS-1 has the dual function of antiinflammatory and neuroprotective.Its chemical constitution is as follows:
Concrete synthetic method sees that people such as Tamas Bartfai was published in the article that PNAS goes up the 7971-7976 page or leaf in 2003.At present, its preventive and therapeutic effect in remodeling ventricle and heart failure is not appeared in the newspapers as yet.
Three, summary of the invention
Technical problem: the present invention is directed to above-mentioned technological gap, a kind of N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group is provided]-3-Phenylpropionamide (hydrocinnamoyl-L-valyl pyrrolidine, purposes AS-1).
Technical scheme: N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-application of 3-Phenylpropionamide (AS-1) in control remodeling ventricle and heart failure medicine.
N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-application of 3-Phenylpropionamide (AS-1) in control inductive myocardial hypertrophy of pressure load and remodeling ventricle medicine.
N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-application of 3-Phenylpropionamide (AS-1) in control acute ischemic heart disease and heart ischemia/reperfusion injury medicine.
Beneficial effect: the present invention is to known compound N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-the 3-Phenylpropionamide excavated new medical application, opened up a new application.
N-[2-methyl isophthalic acid of the present invention-(pyrrolidine-1-carbonic acyl radical)-propyl group]-3-Phenylpropionamide safety non-toxic, pharmacological action is strong, and good prospect in medicine is arranged.
N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-3-Phenylpropionamide (AS-1) can suppress the hypertrophy growth of myocardial cell; improve the fibrosis of myocardial cell; the cardiac function of the heart that raising damages because of pressure load is too high; thereby the hypertrophy and the remodeling ventricle of control myocardial cell delay the generation of heart failure.N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-3-Phenylpropionamide (AS-1) can improve the cardiac function that suffers acute myocardial ischemia and ischemia/reperfusion injury heart; early stage application can reduce the area of infarcted region; reduce the infiltration of inflammatory cell in the cardiac muscular tissue; keep the function of myocardial cell, delay the generation of heart failure.
Four, description of drawings
Figure 1A S-1 influences TAC (aortic arch constriction) postoperative HW/BW (cardiac weight/body weight).★ and Sham organize ratio, P＜0.05, ▲ organize ratio, P＜0.05 with TAC group or DMSO.
Fig. 2 AS-1 influences TAC postoperative HW/BW.★ and Sham organize ratio, P＜0.05, ▲ organize ratio, P＜0.05 with TAC group or DMSO.
Fig. 3 AS-1 is to the influence of TAC postoperative mice interventricular septum diastole thickness.# and Sham organize ratio, P＜0.05, ★ and TAC group or DMSO group ratio, P＜0.05.
Fig. 4 AS-1 to the diastole of TAC postoperative mice left ventricle after the influence of wall thickness.# and Sham organize ratio, P＜0.05, ★ and TAC group or DMSO group ratio, P＜0.05.
Fig. 5 AS-1 is to the influence of TAC postoperative mice ejection fraction.# and Sham organize ratio, P＜0.05, ★ and TAC group or DMSO group ratio, P＜0.05.
Fig. 6 AS-1 is to the influence of TAC postoperative mice shortening fraction.# and Sham organize ratio, P＜0.05, ★ and TAC group or DMSO group ratio, P＜0.05.
Fig. 7 AS-1 is to the influence of TAC postoperative mouse heart outward appearance
Fig. 8 AS-1 is loose and Fibrotic influence to TAC postoperative mouse cardiac muscle cell.Last row, HE dyeing, following row, Masson dyeing.
Fig. 9 AS-1 organizes the influence of p-P38 expression to TAC postoperative mouse cardiac muscle.★ and Sham organize ratio, P＜0.05, ▲ organize ratio, P＜0.05 with TAC group or DMSO.
Figure 10 AS-1 organizes the influence of p-ERK expression to TAC postoperative mouse cardiac muscle.★ and Sham organize ratio, P＜0.05, ▲ organize ratio, P＜0.05 with TAC group or DMSO.
Figure 11 AS-1 organizes the influence of p-JNK expression to TAC postoperative mouse cardiac muscle.★ and Sham organize ratio, P＜0.05, ▲ organize ratio, P＜0.05 with TAC group or DMSO.
Figure 12 AS-1 organizes the influence of NF-kB activity to TAC postoperative mouse cardiac muscle
Figure 13 AS-1 organizes the influence of NF-kB activity to TAC postoperative mouse cardiac muscle.# and Sham organize ratio, P＜0.05, ★ and TAC group or DMSO group ratio, P＜0.05.
Figure 14 AS-1 is to the influence of the myocardial cell area of hypertrophy.
Figure 15 AS-1 is to the synthetic influence of myocardial cell albumen of hypertrophy.★ and Control organize ratio, P＜0.05, ▲ organize ratio, P＜0.05 with IL-1 group or DMSO.
Figure 16 AS-1 is to the influence of the myocardial cell p-P38 expression of hypertrophy.★ and Control organize ratio, P＜0.05, ▲ organize ratio, P＜0.05 with IL-1 group or DMSO.
Figure 17 AS-1 is to the influence of the myocardial cell p-ERK expression of hypertrophy.★ and Control organize ratio, P＜0.05, ▲ organize ratio, P＜0.05 with IL-1 group or DMSO.
Figure 18 AS-1 is to the influence of the myocardial cell p-JNK expression of hypertrophy.★ and Control organize ratio, P＜0.05, ▲ organize ratio, P＜0.05 with IL-1 group or DMSO.
Figure 19 AS-1 is to the influence of the myocardial cell NF-kB activity of hypertrophy.
Figure 20 AS-1 is to the influence of the myocardial cell NF-kB activity of hypertrophy.★ and Control organize ratio, P＜0.05, ▲ organize or the DMSO ratio P＜0.05 with IL-1.
Figure 21 AS-1 is to the influence of mouse heart I/R (ischemia/reperfusion) back ejection fraction.
*With I/R group or DMSO group ratio, P＜0.05.
Figure 22 AS-1 to mouse heart I/R after the influence of shortening fraction.
*With I/R group or DMSO group ratio, P＜0.05.
Figure 23 AS-1 to mouse heart I/R after the influence of heart infarct size.
*With I/R group or DMSO group ratio, P＜0.05.
Figure 24 AS-1 is to the influence of I/R cardiac muscular tissue neutrophil infiltration.Be neutrophilic granulocyte shown in the arrow.
Figure 25 AS-1 is to the influence of the expression of interleukin-11 α in the I/R cardiac muscular tissue.# and Control organize ratio, P＜0.05, ★ and I/R group or DMSO group ratio, P＜0.05.
Figure 26 AS-1 is to the influence of interleukin-11 β expression in the I/R cardiac muscular tissue.# and Control organize ratio, P＜0.05, ★ and I/R group or DMSO group ratio, P＜0.05.
Figure 27 AS-1 is to the influence of the expression of interleukin 6 in the I/R cardiac muscular tissue.# and Control organize ratio, P＜0.05, ★ and I/R group or DMSO group ratio, P＜0.05.
Figure 28 AS-1 is to the influence of the NF-of I/R cardiac muscular tissue kB activity.
Figure 29 AS-1 is to the influence of the NF-of I/R cardiac muscular tissue kB activity.
**P＜0.01，
*P＜0.05。
Five, the specific embodiment
N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-3-Phenylpropionamide (AS-1) is synthetic according to the method for bibliographical information, vacuum drying 24 hours.Preparation in the following manner: AS-12g, DMSO 100ml.AS-1 final concentration 20mg/mL.Before the administration, dilute with normal saline.
Chemical compound of the present invention can be made injection, is used for intravenous drip, intravenous injection, lumbar injection, muscle or subcutaneous injection.Also can be made into oral tablet, capsule etc.
Embodiment 1 (AS-1 is to the inductive remodeling ventricle protective effect observation of pressure load)
Select the male C57BL/6 mice of SPF level for use, in 7 to 8 weeks, be divided into 4 groups at random: sham operated rats (Sham), operation group (TAC), operation+solvent control group (DMSO), operation+administration group (AS-1), every group of 6-8 only.The laggard pedestrian worker's ventilation of mouse anesthesia, the 2-3 intercostal is opened the thoracic cavity in the chest left side, separates aortic arch, and (Transverse aortic constriction TAC), closes the thoracic cavity by unified standard constriction aortic arch.Sham operated rats is not except carrying out the TAC, and all the other operative procedure are fully identical with model group.DMSO and AS-1 group postoperative are promptly through intraperitoneal administration, and once a day, the AS-1 administration concentration is 50mg/kg, and after 2 weeks that continued medication, the muscular tissue of coring carries out every analysis.
1.1 the plump exponential mensuration of mouse cardiac muscle
Mice after 2 weeks is weighed, and anesthesia is carried out two dimensional echocardiogram and detected.Put to death subsequently, open the thoracic cavity fast and take out heart, remove atrial tissue, prune heart by unified standard, use the filter paper suck dry moisture, electronic balance accurately takes by weighing weight and left heart weight whole-heartedly.Its tibia of this treatment with external measures is accurately measured tibia length.Calculate its weight/body weight (HW/BW) whole-heartedly, left ventricle/tibia long (LVW/TL), statistics ratio and the super result of the heart.
Fig. 1, Fig. 2 show TAC2 after week, and TAC and DMSO group HW/BW and LVW/TL obviously increase, and paired Sham compares and has significant difference, the prompting left ventricular hypertrophy with age in week; AS-1 group HW/BW compares then with TAC or DMSO group with LVW/TL and obviously reduces.
Fig. 3, Fig. 4, Fig. 5, Fig. 6 show the ultrasoundcardiogram result, the echo district of TAC2 mouse heart IVS (interventricular septal thickness) and LVPW (Left ventricular posterior wall thickness) after week obviously strengthens, EF (ejection fraction), FS (shortening fraction) obviously descend, prompting left ventricular hypertrophy and with the decline of cardiac function; AS-1 group mice left ventricle, interventricular septum relaxing period thickness obviously reduce, and ejection fraction, shortening fraction raise to some extent.
1.2 pathological examination
1. perusal:
Fig. 7 shows that TAC and DMSO group mouse heart obviously increase, and AS-1 group mouse heart has been compared obvious minimizing with TAC group or DMSO group.
2. light microscopy checking:
To mice myocardium of left ventricle tissue slice, the loose and Fibrotic situation of myocardial cell is observed in row HE dyeing and Masson dyeing.
Fig. 8 shows TAC and the broadening of DMSO group myocardial cell transverse diameter, and intercellular substance increases, and fibrous connective tissue increases.The loose group of loose degree of AS-1 group myocardial cell and fibrosis all alleviates to some extent.
1.3AS-1 induce the NF-κ B of hypertrophic cardiomyopathy and MAPK to express and left ventricular tissues is got in active influence to pressure load, extract endochylema and karyon albumen, with the change of plasmosin analysis MAPK (p-P38, JNK, ERK) expression, get karyon albumen, detect NF-KB in conjunction with activity change.
Fig. 9, Figure 10, Figure 11 show 2 weeks of TAC postoperative, and the Expression of phosphorylated level of p38, ERK1/2 increases, and the phosphorylation level of JNK is compared with the Sham group and do not had significant change; AS-1 can suppress p38, the increase of ERK1/2 expression that TAC causes, to the not obviously influence of p-JNK expression.The DMSO group is compared the phosphorylated protein level with the TAC group does not have significant difference.Figure 12, Figure 13 show that TAC postoperative 2 all NF-κ B of cardiac muscular tissue obviously increase in conjunction with activity, give AS-1 after NF-κ B obviously reduce in conjunction with activity.
Embodiment 2 (AS-1 to hypertrophy former generation myocardial cells effect observation)
In vitro culture myocardial cell method of former generation is as follows: after the disconnected neck dislocation of a cleaning level SD neonatal rat is put to death, get its heart, cut apex digest, centrifugal, containing the DMEM culture medium of 15% calf serum, 37 ℃ of 5%CO
2Cultivate 36-48hr in the incubator, when the observation of cell growing state is better, change liquid, grouping.Experiment is divided into four groups: blank (control) group; The IL-1 stimulating group; IL-1 stimulation+DMSO group; IL-1 stimulation+AS-1 group.The IL-1 irritaiting concentration is 10ng/mL, and AS-1 concentration is 100umol/L.
2.1 the loose degree detecting of myocardial cell
In former generation,, cardiac muscle cells stimulated back 24 hours, detected the myocardial cell area with α-actinin immunofluorescence dyeing, mixed method (1uCi/mL) with the 3H-leucine and detected its albumen and synthesize level.These two kinds of methods can both effectively be assessed the loose degree of myocardial cell.
Figure 14 shows that IL-1 can cause the obvious increase of myocardial cell area; After giving AS-1, its myocardial cell area reduces.Figure 15 shows, IL-1 can cause that myocardial cell albumen synthetic water shows dawn to be increased, give AS-1 after, the synthetic level of albumen descends.
2.2AS-1 former generation myocardial cell NF-κ B and MAPK to hypertrophy express and active influence
In former generation,, cardiac muscle cells stimulated back 24 hours, extracted endochylema and karyon albumen, analyzed the change of MAPK (p-P38, JNK, ERK) expression with plasmosin, got karyon albumen, detected NF-KB in conjunction with activity change.
Figure 16, Figure 17, Figure 18 show that IL-1 stimulates the Expression of phosphorylated level make p38, ERK1/2 to increase, and the phosphorylation level of JNK is compared with the Sham group and do not had significant change; AS-1 can suppress p38, the increase of ERK1/2 expression that IL-1 causes, to the not obviously influence of p-JNK expression.The DMSO group is compared the phosphorylated protein level with the IL-1 group does not have significant difference.Figure 19, Figure 20 show that IL-1 stimulates makes NF-κ B obviously increase in conjunction with activity, give AS-1 after NF-κ B obviously reduce in conjunction with activity.
Embodiment 3 (AS-1 observes the protective effect that acute ischemia pours into mouse heart again)
Select the male C57BL/6 mice of SPF level for use, in 6 to 7 weeks, be divided into 4 groups at random: sham operated rats (Sham), operation group (I/R), operation+solvent control group (DMSO), operation+administration group (AS-1), every group of 6-8 only.The laggard pedestrian worker's ventilation of mouse anesthesia, set up ischemia-reperfusion (ischemia/reperfusion, I/R) model, key step is: the 3-4 intercostal is opened the thoracic cavity in the chest left side, cut off pericardium, recover blood reperfusion by unified standard ligation left anterior descending coronary artery blocking blood flow after 45 minutes, close the thoracic cavity.The abdominal cavity gives DMSO or AS-1 in pouring at once again, and the AS-1 administration concentration is 50mg/kg.Pour into the muscular tissue of coring after 4 hours again and detect every index.
3.1 mouse cardiac muscle ischemic areas and cardiac function detect
Mice is poured into anesthesia after 4 hours again, its cardiac function situation of row echocardiography.Put to death subsequently, open the thoracic cavity fast and take out heart normal saline underwent coronary perfusion flushing blood, ligation left anterior descending coronary artery once more, pour into to understand ischemic region (hazardous area with Evans blue, RA) size, heart tissue is cut into the 5-6 sheet, redyed 20 minutes, take pictures after the formalin fixed with TTC.Calculate IA/LV (infarcted region area/left chamber area), RA/V (dangerous area/left chamber area), IR/RA (infarcted region area/dangerous area) with software analysis, understand the myocardial damage degree.
Figure 21, Figure 22 demonstration gives EF (ejection fraction) and the FS (shortening fraction) that AS-1 can obviously improve mouse heart.Figure 23 shows that giving AS-1 can obviously reduce IA/LV, IR/RA ratio, and to the not influence of RA/LV ratio.
3.2 immunology detection
To mice myocardium of left ventricle tissue slice, the row SABC detects the neutrophil infiltration level.
Figure 24 shows, I/R and DMSO group mouse heart neutrophil infiltration showed increased, and AS-1 can reduce the degree of I/R heart neutrophil infiltration significantly.
3.3 cytokines measurement
Get the left compartment muscle tissue, extract plasmosin, adopt the ELISA method to detect the expression of mouse heart interleukin-11 α, interleukin-11 β, interleukin 6.
Figure 25, Figure 26, Figure 27 show that I/R and DMSO group mouse cardiac muscle organize the expression of interleukin-11 α, interleukin-11 β, interleukin 6 obviously to increase, and AS-1 can obviously reduce the expression of interleukin-11 α, interleukin-11 β, interleukin 6.
3.2AS-1 to acute ischemia-influence of perfused hearts NF-kB activity again
Get the left compartment muscle tissue, extract karyon albumen, detect NF-KB in conjunction with activity change.
Figure 28, Figure 29 show, I/R and DMSO group mouse heart NF-KB bound water show to increase dawn, and AS-1 can obviously reduce mouse heart and organizes NF-KB.
Claims (3)
1.N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-application of 3-Phenylpropionamide (AS-1) in preparation control remodeling ventricle and heart failure medicine.
2.N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-application of 3-Phenylpropionamide (AS-1) in preparation control inductive myocardial hypertrophy of pressure load and remodeling ventricle medicine.
3.N-[2-methyl isophthalic acid-(pyrrolidine-1-carbonic acyl radical)-propyl group]-application of 3-Phenylpropionamide (AS-1) in preparation control acute ischemic heart disease and heart ischemia-reperfusion injury medicine.
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