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6-Acylamino-2-[(alkylsulfonyl)oxy]-1H-isoindole-1,3-dione mechanism-based inhibitors of human leukocyte elastase

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第1期10卷 27-30页

作者： Kerrigan, JE Walters, MC Forrester, KJ Crowder, JB Christopher, LJ Univ S Alabama Dept Chem Mobile AL 36688 USA Rutgers State Univ Coll Pharm Dept Pharmaceut Chem Piscataway NJ 08854 USA

A study of various 2-[(alkylsulfonyl)oxy]-6-substituted-1H-isoindole-1,3-diones' inhibition of chymotrypsin compared to inhibition of HLE reveals that acylamino substitution in the 6-position increases selectivity and potency of these inhibitors for HLE. The best HLE inhibitor in this series was 6-(methylglutaryl)amino-2-[(ethylsulfonyl)oxy]-1H-isoindole-1,3-dione with a k(obs)/[I] = 220,000 M-1 s(-1). (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：糜蛋白酶/拮抗剂和抑制剂吲哚类/化学合成吲哚类/药理学动力学白细胞弹性蛋白酶/拮抗剂和抑制剂蛋白质类/化学合成蛋白质类/药理学丝氨酸蛋白酶抑制剂/化学合成丝氨酸蛋白酶抑制剂/药理学舍平类构效关系人类

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Coumarinic derivatives as mechanism-based inhibitors of α-chymotrypsin and human leukocyte elastase

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BIOORGANIC & MEDICINAL CHEMISTRY 2000年第6期8卷 1489-1501页

作者： Pochet, L Doucet, C Dive, G Wouters, J Masereel, B Reboud-Ravaux, M Pirotte, B Univ Namur FUNDP Dept Pharm B-50000 Namur Belgium Univ Paris 06 Inst Jacques Monod Lab Enzymol Mol & Fonctionnelle Dept Biol Supramol & Cellulaire F-75251 Paris 05 France Univ Paris 07 F-75251 Paris 05 France Univ Liege Ctr Ingn Prot B-4000 Liege Belgium Univ Namur FUNDP Mol Struct Lab B-5000 Namur Belgium Univ Liege Lab Chim Pharmaceut B-4000 Liege Belgium

Novel coumarinic derivatives were synthesized and tested for their inhibitory potency toward alpha-CT and HLE. Cycloalkyl esters and amides were found to be essentially inactive on both enzymes. On the opposite, aromatic esters strongly inactivated alpha-CT whereas HLE was less efficiently inhibited with dichlorophenyl ester derivatives (k(inact)/K-I=4000 M-1 s(-1) for 36). Representative examples of amide, ester, thioester and ketone derivatives were prepared in order to evaluate the influence of the link between the coumarinic ring and the phenyl side chain. The irreversible inactivation of alpha-CT by 6-chloromethyl derivatives should be due to alkylation of a histidine residue as suggested by the amino acid analysis of the modified chymotrypsin. Conversely the inhibition of HLE was transient. Intrinsic reactivity of coumarins has been calculated using a model of a nucleophilic reaction between the ligand and the couple methanol-water. From this calculation, it appears that differences in the inhibitory potency expressed by these molecules cannot only be explained by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：糜蛋白酶/拮抗剂和抑制剂香豆素类/化学香豆素类/药理学结晶学 X线酶抑制剂/化学酶抑制剂/药理学白细胞弹性蛋白酶/拮抗剂和抑制剂磁共振波谱学分光光度法红外线人类

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Reversible drug-induced oxyntic atrophy in rats

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GASTROENTEROLOGY 2000年第6期118卷 1080-1093页

作者： Goldenring, JR Ray, GS Coffey, RJ Meunier, PC Haley, PJ Barnes, TB Car, BD Med Coll Georgia Inst Mol Med & Genet Dept Med Augusta GA 30912 USA Med Coll Georgia Augusta Vet Affairs Med Ctr Augusta GA 30912 USA Med Coll Georgia Dept Surg Augusta GA 30912 USA Med Coll Georgia Dept Cell Biol & Anat Augusta GA 30912 USA DuPont Pharmaceut Corp Newark DE USA Vanderbilt Univ Sch Med Dept Med Nashville TN 37212 USA Vanderbilt Univ Sch Med Dept Cell Biol Nashville TN 37212 USA Cephalon W Chester PA USA

Background & Aims: Oxyntic atrophy is the hallmark of chronic gastritis, Many studies have sought to develop animal models for oxyntic atrophy, but none of them are reversible, We now report that rats administered high doses of DMP 777 demonstrate reversible oxyntic atrophy, Methods: DMP 777 was administered to CD-1 rats by oral gavage (200 mg . kg(-1) . day(-1)). Serum gastrin level, in vivo acid secretion, and gastric histological changes were evaluated in DMP 777-dosed animals. Direct effects of DMP 777 on parietal cells were evaluated by assessment of aminopyrine accumulation into isolated rabbit parietal cells, as well as by assessment of DMP 777 effects on acridine orange fluorescence and H+,K+-adenosine triphosphatase (ATPase) activity in isolated tubulovesicles, Results: Oral dosing with DMP 777 caused a rapid increase in serum gastrin levels and severe hypochlorhydria. DMP 777 inhibited aminopyrine accumulation into rabbit parietal cells stimulated with either histamine or forskolin, DMP 777 reversed a stimulated proton gradient in isolated parietal cell tubulovesicles. Oral dosing with DMP 777 led to rapid loss of parietal cells from the gastric mucosa, In response to the acute loss of parietal cells, there was an increase in the activity of the progenitor zone along with rapid expansion of the foveolar cell compartment. DMP 777 treatment also led to the emergence of bromodeoxyuridine-labeled cells and cells positive for periodic acid-Schiff in the basal region of fundic glands. With extended dosing over 3-6 months, foveolar hyperplasia and oxyntic atrophy were sustained while chief cell, enterochromaffin-like cell, and somatostatin cell populations were decreased. No histological evidence of neoplastic transformation was observed with dosing up to 6 months. Withdrawal of the drug after 3 or 6 months of dosing led to complete restitution of the normal mucosal lineages within 3 months. Conclusions: DMP 777 acts as a protonophore with specificity for parieta

关键词：吖啶橙氨基比林/药代动力学消炎药非甾类/药代动力学萎缩吖丁啶类碳放射性同位素疾病模型动物酶抑制剂/药理学荧光染料胃酸/代谢胃泌素类/血液胃炎/化学诱导胃炎/病理学 H(+)K(+)交换ATP酶/代谢离子载体/药理学白细胞弹性蛋白酶/拮抗剂和抑制剂白细胞弹性蛋白酶/代谢坏死尼日利亚菌素/药理学壁细胞胃/酶学壁细胞胃/代谢壁细胞胃/病理学哌嗪类大鼠 Sprague-Dawley 再生胃/病理学胃/生理学动物男(雄)性兔大鼠

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Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease:: Towards smaller inhibitors

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第20期10卷 2267-2270页

作者： Llinàs-Brunet, M Bailey, M Fazal, G Ghiro, E Gorys, V Goulet, S Halmos, T Maurice, R Poirier, M Poupart, MA Rancourt, J Thibeault, D Wernic, D Lamarre, D Boehringer Ingelheim Canada Ltd Res & Dev Laval PQ H7S 2G5 Canada

Structure-activity studies on a hexapeptide N-terminal cleavage product of a dodecamer substrate led to the identification of very potent and highly specific inhibitors of the HCV NS3 protease/NS4A cofactor peptide complex. The largest increase in potency was accomplished by the introduction of a (4R)-naphthalen-1-yl-4-methoxy substituent to the P2 proline. N-Terminal truncation resulted in tetrapeptides containing a C-terminal carboxylic acid, which exhibited low micromolar activity against the HCV serine protease. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：抗病毒药/化学合成抗病毒药/化学抗病毒药/药理学组织蛋白酶B/拮抗剂和抑制剂糜蛋白酶/拮抗剂和抑制剂药物设计肝炎病毒属/药物作用肝炎病毒属/酶学动力学白细胞弹性蛋白酶/拮抗剂和抑制剂模型分子分子构象寡肽类/化学合成寡肽类/化学寡肽类/药理学胰弹性蛋白酶/拮抗剂和抑制剂蛋白质构象丝氨酸内肽酶类/代谢丝氨酸蛋白酶抑制剂/化学合成丝氨酸蛋白酶抑制剂/化学丝氨酸蛋白酶抑制剂/药理学构效关系猪病毒非结构蛋白质类/拮抗剂和抑制剂动物人类

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Elastase and its physiological inhibitors in ARDS: what decides between inflammatory storm or dead calm?

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EUROPEAN RESPIRATORY JOURNAL 1999年第5期13卷 947-948页

作者： Suter, PM Univ Hosp Geneva Div Surg Intens Care Geneva Switzerland

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Leucine-phenylalanine dipeptide-based N-mesyloxysuccinimides:: Synthesis of all four stereoisomers and their assay against serine proteases

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 1999年第3期9卷 497-500页

作者： Abell, AD Oldham, MD Univ Canterbury Dept Chem Christchurch 1 New Zealand

The four stereoisomers of 3-(N-acetylleucylamino)-3-benzyl-1-[(methylsulfonyl)oxy]succinimide have been prepared and shown to inhibit alpha-chymotrypsin and human neutrophil elastase. The structural and stereochemical features that affect the potency and selectivity of inhibition are discussed. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：糜蛋白酶/拮抗剂和抑制剂二肽类/化学亮氨酸/化学白细胞弹性蛋白酶/拮抗剂和抑制剂苯丙氨酸/化学丝氨酸蛋白酶抑制剂/化学合成丝氨酸蛋白酶抑制剂/化学丝氨酸蛋白酶抑制剂/药理学立体异构现象琥珀酰亚胺类/化学合成琥珀酰亚胺类/化学琥珀酰亚胺类/药理学人类

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Synthesis and in vitro and in vivo evaluation of the 2-(6′methoxy-3′,4′dihydro-1′-naphtyl)-4H-3,1-benzoxazin-4-one as a new potent substrate inhibitor of human leukocyte elastase

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 1999年第9期9卷 1291-1294页

作者： Arcadi, A Asti, C Brandolini, L Caselli, G Marinelli, F Ruggieri, V Univ Aquila Dipartimento Chim Ingn Chim & Mat I-67100 Laquila Italy Dompe Res Ctr I-67100 Laquila Italy

the title 2-vinyl-4H-3,1-benzoxazin-4-one has been synthesised and tested for inhibitory activity against human leukocyte elastase. The compound has shown activity both in vitro towards human sputum elastase and in vi... 详细信息

关键词：苯并恶嗪类剂量效应关系药物半数抑制浓度动力学白细胞弹性蛋白酶/拮抗剂和抑制剂肺/药物作用恶嗪类/化学合成恶嗪类/药理学痰/酶学动物人类小鼠

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Inhibition of neutrophil proteinases by recombinant serpin Lex032 reduces capillary no-reflow in ischemia/reperfusion induced acute pancreatitis

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期290卷 782-788页

作者： Von Dobschuetz, E Hoffmann, T Messmer, K Univ Munich Klinikum Grosshadern Inst Surg Res D-81366 Munich Germany

Because neutrophil proteinases such as elastase and cathepsin G are considered to play a major role in inflammatory tissue damage, the microcirculatory effect of the serine proteinase inhibitor (serpin) Lex032 after ischemia/reperfusion (I/R)-induced pancreatitis was investigated. LeX032 inhibits these proteinases by recombinant combination of alpha(1)-antitrypsin and alpha(1)-antichymotrypsin. Twenty-eight anesthetized rats received either Lex032 or NaCl 0.9% as a control solution during baseline conditions or after 1 h of complete reversible ischemia induced by microclip occlusion of the pancreatic arteries. The number of erythrocyte-perfused capillaries (functional capillary density) and the leukocyte adherence in postcapillary venules were assessed by intravital microscopy 45, 90, and 120 min after administration. In the baseline group, Lex032 increased leukocyte adherence compared with the NaCl 0.9% baseline group, without changing any other parameter. I/R without Lex032 treatment resulted in a 50% reduction in functional capillary density, a 2-fold increase in leukocyte adherence, an increase in interleukin-6 serum concentration, and a significant fall in blood pressure during reperfusion time compared with baseline animals. Treatment with Lex032 in I/R resulted in significant preservation of capillary perfusion, an absence of interleukin-6 increase, and preservation of mean arterial pressure during reperfusion time, without changing the leukocyte adherence, compared with the NaCl 0.9% I/R group. Because of its considerable amelioration of microcirculatory perfusion, Lex032 might be useful in the treatment of pancreatic I/R tissue damage (e.g., cardiac bypass surgery, pancreas transplantation, and hemorrhagic shock) by prevention of capillary perfusion failure.

关键词：酸碱平衡/药物作用急性病毛细血管细胞黏附/药物作用趋化性白细胞/药物作用内皮血管/药物作用内皮血管/生理学粒细胞/药物作用血细胞比容白细胞介素6/血液白细胞弹性蛋白酶/拮抗剂和抑制剂白细胞/药物作用白细胞/生理学微循环/药物作用胰腺/血液供给胰腺/药物作用胰腺炎/病因学胰腺炎/病理学胰腺炎/预防和控制大鼠 Sprague-Dawley 重组蛋白质类/药理学再灌注损伤/并发症再灌注损伤/病理学丝氨酸蛋白酶抑制剂/药理学舍平类/药理学 α淀粉酶/代谢动物男(雄)性大鼠

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Molecular structure of FR901277, a novel inhibitor of human leukocyte elastase, and its binding mode simulation

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 1999年第16期9卷 2397-2402页

作者： Nakanishi, I Kinoshita, T Tada, T Fujita, T Hatanaka, H Sato, A Fujisawa Pharmaceut Co Ltd Basic Res Labs Yodogawa Ku Osaka 5328514 Japan Fujisawa Pharmaceut Co Ltd Analyt Res Labs Yodogawa Ku Osaka 5328514 Japan Fujisawa Pharmaceut Co Ltd Exploratory Res Labs Yodogawa Ku Osaka 5328514 Japan

X-ray crystal structure analysis of FR901277, a novel inhibitor of human leukocyte elastase, was performed and revealed that the lipophilic side chains are located towards the outside of the molecule. Binding simulation using computational methods showed that these lipophilic moieties could bind to the hydrophobic binding pockets of HLE. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：酰胺类/化学酰胺类/代谢酰胺类/药理学结合部位结晶学 X线酶抑制剂/化学酶抑制剂/代谢酶抑制剂/药理学白细胞弹性蛋白酶/拮抗剂和抑制剂白细胞弹性蛋白酶/代谢模型分子分子结构蛋白质结合人类

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Destruction of articular cartilage by alpha₂ macroglobulin elastase complexes:: role in rheumatoid arthritis

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ANNALS OF THE RHEUMATIC DISEASES 1999年第2期58卷 109-113页

作者： Moore, AR Appelboam, A Kawabata, K Da Silva, JAP D'Cruz, D Gowland, G Willoughby, DA St Bartholomews & Royal London Sch Med & Dent Dept Expt Pathol London EC1M 6BQ England

Objective-Neutrophil elastase accounts for the ability of some fresh rheumatoid synovial fluids to degrade cartilage matrix in vitro. The aim of this study was to determine if enzyme activity could result from depletion of synovial fluid inhibitors or protection of the enzyme from inhibition. Methods-The ability of synovial fluids to inhibit porcine pancreatic elastase was investigated together with chemical pretreatments capable of inactivating alpha, protease inhibitor (alpha(1)PI) or preventing formation of alpha, macroglobulin (alpha(2)M) elastase complexes. Subsequently, complexes of human neutrophil elastase with alpha(2)M were prepared and applied to frozen sections of cartilage. Proteoglycan loss was quantified by alcian blue staining and scanning and integrating microdensitometry. Parallel studies were carried out using a low molecular weight chromogenic elastase substrate. The effects of alpha(1)PI and SF on these systems were investigated. Finally, synovial fluids were subjected to gel filtration and the fractions assayed for elastase activity. High molecular weight fractions were pooled, concentrated, and tested for their ability to degrade cartilage sections. Results-All synovial fluids reduced the activity of porcine pancreatic elastase, the inhibition mainly being attributable to alpha(1)PI, whereas remaining activity resulted from complexes of elastase with alpha(2)M. Complexes of human neutrophil elastase with alpha(2)M were shown to cause proteoglycan degradation in frozen sections of human articular cartilage. Alpha(1)PI prevented alpha(2)M elastase complexes from degrading cartilage but not the chromogenic substrate. The data suggested that alpha(1)PI does not inhibit elastase bound to alpha(2)M but sterically hinders the complex. However, only one of five synovial fluids was able to completely block the actions of alpha(2)M elastase complexes against cartilage. Gel filtration of rheumatoid synovial fluids showed elastase and cartilage degrading

关键词：关节炎类风湿/代谢软骨关节/代谢色谱法色谱法凝胶膝关节白细胞弹性蛋白酶/拮抗剂和抑制剂白细胞弹性蛋白酶/代谢蛋白质结合蛋白聚糖类/代谢滑液/酶学滑液/代谢 α1抗胰蛋白酶/代谢 α巨球蛋白类/代谢成年人人类

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