Inhibition of allergen-induced pulmonary responses by the selective tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy]-pen tane (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 associated 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]-p henoxy]-pentane (AMG-126737) was evaluated for its pharmacologic effects against allergen-induced airway responses. AMG-126737 is a potent inhibitor of human lung mast cell tryptase (Ki = 90 nM), with greater than 10- to 200-fold selectivity versus other 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 confirmed in a sheep model of allergen-induced airway responses, where the compound inhibited early and late phase bronchoconstriction responses and the development of airway hyperresponsiveness. These results support the proposed role of tryptase in the pathology of asthma and suggest that AMG-126737 has potential therapeutic utility in this pulmonary disorder.
Wright
C D
CD
Department of Inflammation Research, Amgen, Inc., Boulder, CO 80301, USA. cwright@amgen.com
Havill
A M
AM
Middleton
S C
SC
Kashem
M A
MA
Dripps
D J
DJ
Abraham
W M
WM
Thomson
D S
DS
Burgess
L E
LE
D000485:Allergens; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use*; D053818:Chymases; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology*; D010420:Pentanes / Q000494:pharmacology / Q000627:therapeutic use*; D012129:Respiratory Function Tests; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000188:drug therapy; D012697:Serine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D012756:Sheep; D053802:Tryptases
C402023:1,5-bis-(4-((3-carbamimidoyl-benzenesulfonylamino)-methyl)-phenoxy)-pentane; D000485:Allergens; D018927:Anti-Asthmatic Agents; D002219:Carbamates; D004791:Enzyme Inhibitors; D010420:Pentanes; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases