Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA).
In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound 1, a significant change provided compounds in which the amidine, binding in the S1 pocket, was replaced with a primary amine. Further modifications led to the identification of potent, selective, and orally bioavailable uPA inhibitors.
West
Christopher W
CW
Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. cwest@icagen.com
Adler
Marc
M
Arnaiz
Danny
D
Chen
Deborah
D
Chu
Kieu
K
Gualtieri
Giovanna
G
Ho
Elena
E
Huwe
Christoph
C
Light
David
D
Phillips
Gary
G
Pulk
Rebecca
R
Sukovich
Drew
D
Whitlow
Marc
M
Yuan
Shendong
S
Bryant
Judi
J
D000284:Administration, Oral; D000578:Amidines / Q000737:chemistry; D000818:Animals; D001596:Benzylamines / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000578:Amidines; D001596:Benzylamines; D015842:Serine Proteinase Inhibitors; C030796:benzylamine; D014568:Urokinase-Type Plasminogen Activator