SUBSTITUTED N-(SULFONYL)OXY PHTHALIMIDE INHIBITORS OF HL

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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.