SUBSTITUTED N-(SULFONYL)OXY PHTHALIMIDE INHIBITORS OF HL

肺气肿和慢性支气管炎是两个主要组成部分， 慢性阻塞性肺疾病（COPD），一个严重的健康问题 在全世界都有。 随着美国人口老龄化，COPD 正稳步上升为死亡的主要原因 人类白细胞 弹性蛋白酶（HLE）已被牵连作为一个致病因子在疾病 被称为肺气肿。 HLE的高度特异性抑制是可能的。 “替代疗法”的手段，为那些缺乏 α-1-抗胰蛋白酶（天然抑制剂）。 长期目标是 研究是开发具有最小副作用的药物， 有效治疗慢性阻塞性肺疾病（COPD）。 的 在这一努力中的目标将通过基于结构的设计来实现 approach. 一类有前途的丝氨酸抑制剂 蛋白酶是N-磺酰基）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 的特异性 在2-（（烷基磺酰基）氧基）-6-（4-（三氟甲基）苯基）-2-（（三氟甲基）苯基）氨基甲酰基）氨基甲酸酯中引入取代基 取代的-1H-异吲哚-1，3（2 H）-二酮将用于利用 二级特异性和提高这些高度的选择性 HLE的有效抑制剂 初期工作将集中在收购 通过分子建模和蛋白质消化 共价酶抑制剂复合物的研究，随后测定 影响新化合物的效力和选择性的结构特征 2-（（烷基磺酰基）氧基）-6-取代的-1H-异吲哚-1，3（2 H）-二酮 相对于其他丝氨酸蛋白酶的HLE。 新型结构的引线将 从非共价酶抑制剂的分子模拟发展而来 配合物

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.