Dibasic inhibitors of human mast cell tryptase. Part 2: structure-activity relationships and requirements for potent activity.
Detailed structure activity relationships (SARs) for a series of dibasic human tryptase inhibitors are presented. The structural requirements for potent inhibitory activity are remarkably broad with a range of core template modifications being well tolerated. Optimized inhibitors demonstrate potent anti-asthmatic activity in a sheep model of allergic asthma. APC-2059, a dibasic tryptase inhibitor with subnanomolar activity, has been advanced to phase II clinical trials for the treatment of both psoriasis and ulcerative colitis.
Rice
K D
KD
Department of Medicinal Chemistry, Axys Pharmaceuticals, Inc., South San Francisco, CA 94080, USA.
Wang
V R
VR
Gangloff
A R
AR
Kuo
E Y
EY
Dener
J M
JM
Newcomb
W S
WS
Young
W B
WB
Putnam
D
D
Cregar
L
L
Wong
M
M
Simpson
P J
PJ
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012756:Sheep; D013329:Structure-Activity Relationship; D053802:Tryptases
D018927:Anti-Asthmatic Agents; D003959:Diamines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053802:Tryptases