Effect of the leukotriene A4 hydrolase aminopeptidase augmentor 4-methoxydiphenylmethane in a pre-clinical model of pulmonary emphysema

被引：20

作者：

De Oliveira, Eliseu O. ^{[2
]}

Wang, Kan ^{[2
]}

Kong, Hye-Sik ^{[2
]}

Kim, Suhyon

Miessau, Matthew ^{[2
]}

Snelgrove, Robert J. ^{[3
]}

Shim, Y. Michael ^{[1
]}

Paige, Mikell ^{[2
]}

机构：

[1] Univ Virginia, Div Pulm & Crit Care Med, Dept Med, Sch Med, Charlottesville, VA 22908 USA

[2] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA

[3] Univ London Imperial Coll Sci Technol & Med, Leukocyte Biol Sect, Natl Heart & Lung Inst, London SW7 2AZ, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 22期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

Emphysema; COPD; LTB4; Aminopeptidase; Leukotriene A4 hydrolase; Murine model; CYSTIC-FIBROSIS; RHEUMATOID-ARTHRITIS; ALPHA-1-ANTITRYPSIN DEFICIENCY; NEUTROPHILIC INFLAMMATION; BRONCHIAL INFLAMMATION; ALVEOLAR MACROPHAGES; ULCERATIVE-COLITIS; POTENTIAL ROLE; B-4; PRODUCTION; INHIBITOR;

D O I：

10.1016/j.bmcl.2011.09.048

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The leukotriene A(4) hydrolase enzyme is a dual functioning enzyme with the following two catalytic activities: an epoxide hydrolase function that transforms the lipid metabolite leukotriene A(4) to leukotriene B-4 and an aminopeptidase function that hydrolyzes short peptides. To date, all drug discovery efforts have focused on the epoxide hydrolase activity of the enzyme, because of extensive biological characterization of the pro-inflammatory properties of its metabolite, leukotriene B-4. Herein, we have designed a small molecule, 4-methoxydiphenylmethane, as a pharmacological agent that is bioavailable and augments the aminopeptidase activity of the leukotriene A(4) hydrolase enzyme. Pre-clinical evaluation of our drug showed protection against intranasal elastase-induced pulmonary emphysema in murine models. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：6746 / 6750

页数：5

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