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SUBSTITUTED N-(SULFONYL)OXY PHTHALIMIDE INHIBITORS OF HL

HL 取代的 N-(磺酰)氧基邻苯二甲酰亚胺抑制剂

基本信息

批准号：
2031395
负责人：
JOHN E KERRIGAN
金额：
$ 2.96万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 1997-08-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2031395
关键词：
alpha 1 antitrypsin chemical models chronic obstructive pulmonary disease computer simulation drug design /synthesis /production elastase inhibitor elastases enzyme structure phthalimides serine proteinases

项目摘要

Pulmonary emphysema and chronic bronchitis are the two main components of Chronic Obstructive Pulmonary Disease (COPD), a serious health problem throughout the world. As the population in the United States ages, COPD is steadily increasing as a leading cause of death. Human leukocyte Elastase (HLE) has been implicated as a causative agent in the disease state known as emphysema. Highly specific inhibition of HLE is a possible means of "replacement therapy" for those individuals who are deficient in alpha-1-antitrypsin (a natural inhibitor). The long-term goal of this research is the development of drugs possessing minimal side effects for the effective treatment Chronic Obstructive Pulmonary Disease (COPD). The goal in this effort will be accomplished via a structure-based design approach. One promising class of mechanism-based inhibitors of serine proteases is the N-Sulfonyl)oxyphthalimides (isoindole-1,3-diones). These compounds are effective inhibitors of HLE in vitro; however, they lack specificity. Incorporation of substituents in 2-((alkylsulfonyl)oxy)-6- substituted-1H-isoindole-1,3(2H)-diones will be used to take advantage of secondary specificity and improve the selectivity of these highly effective inhibitors for HLE. Initial work will focus on the acquisition of structural information through molecular modeling and protein digest studies of covalent enzyme-inhibitor complexes followed by determination of structural features that influence the potency and selectivity of novel 2-((alkylsulfonyl)oxy)-6-substituted-1H-isoindole-1,3(2H)-diones for the HLE relative to other serine proteases. novel structure leads will be developed from molecular modeling of non-covalent enzyme-inhibitor complexes.

肺气肿和慢性支气管炎是慢性阻塞性肺疾病(COPD)，一个严重的健康问题在世界各地。随着美国人口老龄化，慢性阻塞性肺病正在稳步上升，成为主要的死亡原因。人白细胞弹性蛋白酶(HLE)被认为是该病的致病因素。称为肺气肿的状态。HLE的高度特异性抑制是一种可能的 “替代疗法”的手段，为那些有缺陷的人。 α-1-抗胰蛋白酶(一种天然抑制剂)。这样做的长期目标是研究人员正在开发副作用最小的药物有效治疗慢性阻塞性肺疾病(COPD)这个这项工作的目标将通过基于结构的设计来实现接近。一类很有前途的丝氨酸机制抑制剂蛋白水解酶是N-磺酰氧基邻苯二甲酰亚胺(异吲哚-1，3-二酮)。这些化合物在体外是HLE的有效抑制剂；然而，它们缺乏专一性。2-((烷基磺酰基)氧基)-6-取代基的掺入取代的-1H-异吲哚-1，3(2H)-二酮将被用于利用二次特异性和提高这些高度的选择性 HLE的有效抑制剂。初步工作将集中在收购上通过分子建模和蛋白质消化获得结构信息共价酶-抑制剂络合物的研究及测定影响小说的效力和选择性的结构特征 2-((alkylsulfonyl)oxy)-6-substituted-1H-isoindole-1，3(2H)-diones适用于 HLE相对于其他丝氨酸蛋白酶。新结构的引线将是非共价酶抑制剂的分子模拟研究进展复合体。