Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 2. Exploring interactions at the proximal (S2) binding site.
In an effort to increase the thrombin inhibitory activity of a novel series of inhibitors (i.e., 1a), substituents were incorporated at the C-3" position of the C-3 aryl ring (2). Consistent with the X-ray crystallography studies, small hydrophobic groups at the C-3" site (Br and Me) enhanced thrombin inhibitory activity by 8-fold. However, a few more hydrophilic substituents (NO2 and OMe) also enhanced the potency of the series. The biological results are discussed in terms of molecular modeling studies.
Sall
D J
DJ
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Briggs
S L
SL
Chirgadze
N Y
NY
Clawson
D K
DK
Gifford-Moore
D S
DS
Klimkowski
V J
VJ
McCowan
J R
JR
Smith
G F
GF
Wikel
J H
JH
D001665:Binding Sites; D018360:Crystallography, X-Ray; D008956:Models, Chemical; D008958:Models, Molecular; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*
D015842:Serine Proteinase Inhibitors; D013876:Thiophenes; C088015:benzothiophene; D013917:Thrombin