Potent selective nonpeptidic inhibitors of human lung tryptase

Human lung tryptase, a homotetrameric serine protease unique to mast cell s ecretory granules, has been implicated in the pathogenesis of asthma. A hyp othesis that tethered symmetrical inhibitors might bridge two adjacent acti ve sites was explored via a rationally designed series of bisbenzamidines. These compounds demonstrated a remarkable distanced-defined structure-activ ity relationship against human tryptase with one series possessing subnanom olar potencies. Additional evidence supporting the concept of active-site b ridging is also presented.