SBIR-STTR Award

Tryptase is a major protease in human mast cells. Evidence indicates that tryptase may be important in neuropeptide processing and tissue inflammation in the lungs. The purpose of this study is to synthesize three analogs of an initial aromatic amidine tryptase inhibitor BABIM [bis(5-amidino-2-benzimidazolyl) methane] and determine their activity in cellular and ex vivo bioassays. The ability of the compounds to inhibit tryptase in a biochemical assay as well as the tryptase-mediated hydrolysis of bronchoactive peptides and tryptase-mediated stimulation of fibroblast mitogenesis in vitro will be determined. In addition, the ability of the most promising compound to prevent in vivo airway hyperresponsiveness in a dog model of asthma will be determined. Molecular modeling techniques will be used to continue the design of new analogs with increased activity against tryptase. These studies will determine if the development of tryptase inhibitors will be potentially useful for the treatment of airway hyperresponsiveness of asthma.