Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors.
A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with but possessing improved solubility.
Rudolph
M Jonathan
MJ
3-Dimensional Pharmaceuticals Inc., 665 Stockton Drive, Exton, PA 19341, USA. rudolph@3dp.com
Illig
Carl R
CR
Subasinghe
Nalin L
NL
Wilson
Kenneth J
KJ
Hoffman
James B
JB
Randle
Troy
T
Green
David
D
Molloy
Chris J
CJ
Soll
Richard M
RM
Lewandowski
Frank
F
Zhang
Marie
M
Bone
Roger
R
Spurlino
John C
JC
Deckman
Ingrid C
IC
Manthey
Carl
C
Sharp
Celia
C
Maguire
Diane
D
Grasberger
Bruce L
BL
DesJarlais
Renée L
RL
Zhou
Zhao
Z
D000478:Alkylation; D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D018020:Lithium Compounds / Q000737:chemistry; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; 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; D007202:Indicators and Reagents; D018020:Lithium Compounds; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D013876:Thiophenes; D014568:Urokinase-Type Plasminogen Activator