Interaction with the S1 beta-pocket of urokinase: 8-heterocycle substituted and 6,8-disubstituted 2-naphthamidine urokinase inhibitors.
Several 8-substituted 2-naphthamidine-based inhibitors of the serine protease urokinase plasminogen activator (uPA) are described. Direct attachment of five-membered saturated or unsaturated rings improved inhibitor performance; substitution with sulfones further improved binding profiles. Combination of these substituents or of previously described NH-linked heteroaromatic rings with 6-phenyl amide substituents provided further enhancements to potency and selectivity.
Wendt
Michael D
MD
Cancer Research, Global Pharmaceutical R & D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA. mike.d.wendt@abbott.com
Geyer
Andrew
A
McClellan
William J
WJ
Rockway
Todd W
TW
Weitzberg
Moshe
M
Zhao
Xumiao
X
Mantei
Robert
R
Stewart
Kent
K
Nienaber
Vicki
V
Klinghofer
Vered
V
Giranda
Vincent L
VL
D001798:Blood Proteins / Q000737:chemistry* / Q000378:metabolism; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001798:Blood Proteins; D009281:Naphthalenes; D015842:Serine Proteinase Inhibitors; C031220:urokinase inhibitor; C018609:beta-naphthamidine; D014568:Urokinase-Type Plasminogen Activator