Synthesis of thiophene-2-carboxamidines containing 2-aminothiazoles and their biological evaluation as urokinase inhibitors.
The serine protease urokinase (uPa) has been implicated in the progression of both breast and prostate cancer. Utilizing structure based design, the synthesis of a series of substituted 4-[2-amino-1,3-thiazolyl]-thiophene-2-carboxamidines is described. Further optimization of this series by substitution of the terminal amine yielded urokinase inhibitors with excellent activities.
Wilson
K J
KJ
3-Dimensional Pharmaceuticals, Inc., Exton, PA 19341, USA. wilson@3dp.com
Illig
C R
CR
Subasinghe
N
N
Hoffman
J B
JB
Rudolph
M J
MJ
Soll
R
R
Molloy
C J
CJ
Bone
R
R
Green
D
D
Randall
T
T
Zhang
M
M
Lewandowski
F A
FA
Zhou
Z
Z
Sharp
C
C
Maguire
D
D
Grasberger
B
B
DesJarlais
R L
RL
Spurlino
J
J
D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
D000578:Amidines; D013844:Thiazoles; D013876:Thiophenes; C004483:2-aminothiazole; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator