Low molecular weight inhibitors of human neutrophil elastase and human neutrophil myeloperoxidase

It is currently accepted that the existence of an imbalance between proteinases and their physiological inhibitors is associated with various pathological states, most notably pulmonary emphysema, chronic bronchitis and cystic fibrosis. The existence of a proteinase/antiproteinase imbalance can lead to lung damage via the degradative action of proteinases on components of lung connective tissue. Damage to connective tissue appears to be mediated primarily by neutrophil elastase, although other proteinases released by the phagocytic cells have also been implicated. The inactivation of alpha-1-proteinase inhibitor, a major physiological inhibitor of neutrophil elastase, is mediated by endogenous oxidants (derived from the myeloperoxidase and the "respiratory burst" oxidase system) and exogenous oxidants (derived from cigarette smoke). The oxidative process decreases the proteinase inhibitor screen and also increases the proteinase burden in the lungs through neutrophil recruitment and degranulation.;A rational therapeutic approach aimed at reestablishing a proteinase/anti-proteinase balance lies in the design of compounds that can protect from the increased proteolytic burden and/or inhibit the oxidative inactivation of the physiological proteinase inhibitors.;This thesis describes the synthesis and in-vitro biochemical evaluation of different series of compounds that (a) inhibit human neutrophil elastase, a major enzyme involved in chronic obstructive lung disease, (b) incorporate an antioxidant component in their structure, and (c) inhibit human neutrophil myeloperoxidase (MPO), an enzyme involved in oxidant generation.;Phosphate esters of N-hydroxysuccinimide derivatives and alkylthiosuccinimide derivatives were found to be highly effective, time-dependent, irreversible inhibitors of human leukocyte elastase (HLE). Structure-activity relationship studies with the alkylthiosuccinimide derivatives indicate that the oxidation of thioether type of compounds results in the generation of a more potent inhibitor of HLE, and the simultaneous scavenging of an oxidant molecule.;A series of imidazole and triazole compounds were evaluated for inhibitory activity towards myeloperoxidase. These compounds were found to be competitive inhibitors of the enzyme. They constitute a new class of competitive inhibitors of MPO.