Inhibition of allergen-induced pulmonary responses by the selective tryptase inhibitor 1,5-bis-{4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]phenoxy}-pentane (AMG-126737)

Emerging evidence suggests that mast cell tryptase is a therapeutic target for the treatment of asthma. The effects of this serine protease are associ ated with both pathophysiologic pulmonary responses and pathologic changes of the asthmatic airway. In this study, the tryptase inhibitor 1,5-bis-{4-[ (3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy}-pentane (AMG-126737 ) was evaluated for its pharmacologic effects against allergen-induced airw ay responses. AMG-126737 is a potent inhibitor of human lung mast cell tryp tase (K-i = 90 nM), with greater than 10- to 200-fold selectivity versus ot her serine proteases. Intratracheal administration of AMG-126737 inhibited the development of airway hyperresponsiveness in allergen-challenged guinea pigs with an ED50 of 0.015 mg/kg. In addition, the compound exhibited oral activity in the guinea pig model. The in vivo activity of AMG-126737 was c onfirmed in a sheep model of allergen-induced airway responses, where the c ompound inhibited early and late phase bronchoconstriction responses and th e development of airway hyperresponsiveness. These results support the prop osed role of tryptase in the pathology of asthma and suggest, that AMG-1267 37 has potential therapeutic utility in this pulmonary disorder. (C) 1999 E lsevier Science Inc.