Potent selective nonpeptidic inhibitors of human lung tryptase.
Human lung tryptase, a homotetrameric serine protease unique to mast cell secretory granules, has been implicated in the pathogenesis of asthma. A hypothesis that tethered symmetrical inhibitors might bridge two adjacent active sites was explored via a rationally designed series of bisbenzamidines. These compounds demonstrated a remarkable distanced-defined structure-activity relationship against human tryptase with one series possessing subnanomolar potencies. Additional evidence supporting the concept of active-site bridging is also presented.
Array BioPharma, 1885 33rd Street, Boulder, CO 80301, USA.
L E
LE
Burgess
B J
BJ
Newhouse
P
P
Ibrahim
J
J
Rizzi
M A
MA
Kashem
A
A
Hartman
B J
BJ
Brandhuber
C D
CD
Wright
D S
DS
Thomson
G P
GP
Vigers
K
K
Koch
D001249:Asthma / Q000209:etiology; D001550:Benzamidines / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D053818:Chymases; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000201:enzymology*; D008407:Mast Cells / Q000201:enzymology; D015394:Molecular Structure; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D053802:Tryptases
D001550:Benzamidines; D004791:Enzyme Inhibitors; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases