This project has as its objectives for Phase I and Phase II the design, synthesis and preclinical evaluation of orally bioavailable, small molecule, non-peptide inhibitors of human leukocyte elastase (HLE) (EC 3.4.21.37) as potential therapeutic agents. A growing body of evidence indicates that this enzyme participates in a variety of pathophysiological processes that include emphysema, rheumatoid arthritis, adult respiratory distress syndrome (ARDS), glomerulonephritis, and cystic fibrosis. Many of these disease areas represent a significant unmet therapeutic need. Hence, an orally bioavailable HLE inhibitor would be an attractive candidate for Phase III of this project: clinical development, FDA registration and marketing in partnership with a large pharmaceutical firm. ImmunoPharmaceutics will employ the methodology it has developed to design small molecule drugs based on the structure of inhibitory antibodies to enzymes--methods that are especially applicable to human enzymes. The initial experimental protocols are based on the expertise we have gained through preliminary studies on raising murine antibodies to HLE for use as drug design templates. Subsequent protocols are based on our studies of the computer docking of antagonist antibodies with the aspartic protease renin, and our design and synthesis of small molecule endothelin antagonists.
