MECHANISM-BASED ELASTASE INHIBITORS

SYNTHETIC ELASTASE INHIBITORS FOR USE IN THE TREATMENT OF EMPHYSEMA WILL BE DEVELOPED. IN PHASE I, NEW MECHANISM-BASED ELASTASE INHIBITORS WILL BE SYNTHESIZED, CHARACTERIZED, AND STUDIED AS INHIBITORS OF ELASTASE IN VITRO. THESE INHIBITION STUDIES WILL ANALYZE BOTH THE REVERSIBLE BEHAVIOR OF THE INHIBITORS AND THE TIME-DEPENDENT, IRREVERSIBLE ELASTASE INACTIVATION. AFTER THE CHEMISTRY OF THE ELASTASE INACTIVATION HAS BEEN ELUCIDATED IN PHASE I, A STRUCTURE-ACTIVITY STUDY WILL BE CARRIED OUT IN PHASE II TO DEVELOP THE MOST POTENT ELASTASE INHIBITORS. BECAUSE THE ABSENCE OF NATURAL ELASTASE INHIBITORS IN THE LUNG IS BELIEVED TO BE RESPONSIBLE FOR MUCH OF THE PATHOGENESIS OBSERVED IN EMPHYSEMA, THESE NEW SYNTHETIC ELASTASE INHIBITORS SHOULD BE VERY VALUABLE FOR USE IN REPLACEMENT THERAPY FOR PATIENTS WITH EMPHYSEMA.