人白细胞弹性蛋白酶的抑制作用。2. 取代头孢菌素酯和酰胺的抑制作用。

Inhibition of human leukocyte elastase. 2. Inhibition by substituted cephalosporin esters and amides.

作者信息

Finke P E, Ashe B M, Knight W B, Maycock A L, Navia M A, Shah S K, Thompson K R, Underwood D J, Weston H, Zimmerman M

机构信息

Department of Medicinal Chemical Research, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.

出版信息

J Med Chem. 1990 Sep;33(9):2522-8. doi: 10.1021/jm00171a029.

DOI:10.1021/jm00171a029

PMID:2391692

Abstract

A variety of 7 alpha-methoxycephalosporin ester and amide sulfones were prepared and tested to determine the structure-activity relations for inhibition of human leukocyte elastase (HLE), a serine protease which has been implicated in several degenerative lung and tissue diseases. The most potent IC50 values were obtained with neutral, lipophilic derivatives, with the esters being more active than the amides. However, the best time-dependent inhibition in this series was observed with the p- and m-carboxybenzyl esters 7b and 7c. These results are discussed in terms of the proposed mechanism of inhibition as well as a molecular modeling study using the recently solved X-ray crystal structure of HLE.

摘要

制备并测试了多种7α-甲氧基头孢菌素酯和酰胺砜，以确定其对人白细胞弹性蛋白酶（HLE）抑制作用的构效关系。HLE是一种丝氨酸蛋白酶，与多种肺部和组织退行性疾病有关。中性亲脂性衍生物的半数抑制浓度（IC50）值最高，其中酯类比酰胺类更具活性。然而，在该系列中，对羟基苯甲酸苄酯7b和间羟基苯甲酸苄酯7c表现出最佳的时间依赖性抑制作用。根据提出的抑制机制以及利用最近解析的HLE X射线晶体结构进行的分子模拟研究对这些结果进行了讨论。