PEPTIDYL ALPHA-KETOHETEROCYCLIC INHIBITORS OF HUMAN NEUTROPHIL ELASTASE .3. IN-VITRO AND IN-VIVO POTENCY OF A SERIES OF PEPTIDYL ALPHA-KETOBENZOXAZOLES
PEPTIDYL ALPHA-KETOHETEROCYCLIC INHIBITORS OF HUMAN NEUTROPHIL ELASTASE .3. IN-VITRO AND IN-VIVO POTENCY OF A SERIES OF PEPTIDYL ALPHA-KETOBENZOXAZOLES
复制标题
DOI：
10.1021/jm00020a011
复制
发表时间：
1995-09-29
影响因子：
7.3
通讯作者：
TUTHILL, PA
中科院分区：
文献类型：
--
作者：
EDWARDS, PD;ZOTTOLA, MA;TUTHILL, PA
合成了一系列多肽基α-酮基苯并恶唑类化合物，并研究了它们在体外和体内对人中性粒细胞弹性蛋白酶(HNE)的抑制作用。这些化合物通过在酮羰基碳原子和Ser-195的羟基之间形成共价键以及在苯并恶唑氮原子和His-57之间形成氢键来抑制HNE。在母体苯并恶唑环上添加了多种取代基，这些取代基跨越了一系列物理化学性质，但对体外效力的影响不大(K-I=3-0.4 nm)。这种明显缺乏显著影响的原因被认为是这样一个事实，即环取代基增加的酮酮基活化被苯并恶唑氮原子氢键能力的相应下降所抵消。与体外结果相反，VIVE活性的最大化关键取决于苯并恶唑环取代基的选择。几种取代的多肽基α-酮苯并恶唑能有效地抑制HNE诱导的肺损伤，在该酶作用前24小时气管内给药。
A series of peptidyl alpha-ketobenzoxazoles were synthesized and evaluated for their in vitro and in vivo inhibition of human neutrophil elastase (HNE). These compounds inhibit HNE by forming both a covalent bond between the ketone carbonyl carbon atom and the hydroxyl group of Ser-195 and a hydrogen bond between the benzoxazole nitrogen atom and His-57. Appending to the parent benzoxazole ring a variety of substituents which spanned a range of physicochemical properties had only a modest effect on in, vitro potency (K-i = 3-0.4 nM). This apparent lack of a significant effect is believed to result from the fact that any increased ketone carbonyl activation by the ring substituent is counter balanced by a corresponding decrease in the hydrogen-bonding ability of the benzoxazole nitrogen atom. In contrast to the results in vitro, maximizing in vive activity was critically dependent upon the choice of the benzoxazole ring substituent. Several substituted peptidyl alpha-ketobenzoxazoles effectively inhibited HNE-induced lung injury when administered intratracheally 24 h prior to the enzyme.