Design and Synthesis of Oral Elastase Inhibitors

The objectives for Phase I and Phase II are the design, synthesis and preclinical evaluation oforally bioavailable, small molecule, non-peptide inhibitors of human leukocyte elastase (HLE)(EC3.4.21.37) as potential therapeutic agents. A growing body of evidence indicates that this enzymeparticipates in a variety of pathophysiological processes that include emphysema, rheumatoid arthritis,adult respiratory distress syndrome (ARDS), glomerulonephritis, and cystic fibrosis. Many of thesedisease areas represent a significant unmet therapeutic need. Hence, an orally bioavailable HLE inhibitorwould be an attractive candidate for Phase III of this project: clinical development, FDA registration andmarketing in partnership with a large pharmaceutical firm. We will employ the methodology it hasdeveloped to design small molecule drugs based on the structure of inhibitory antibodies toenzymes--methods that are especially applicable to human enzymes. The initial experimental protocolsare based on the expertise we have gained through preliminary studies on raising murine antibodies toHLE for use as drug design templates. Subsequent protocols are based on our studies of the computerdocking of antagonist antibodies with the aspartic protease renin, and our design and synthesis of smallmolecule endothelin antagonists.