Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 2. Sidechain optimization and demonstration of in vivo efficacy.
Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis.
Zhang
M
M
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Bailey
D L
DL
Bastian
J A
JA
Briggs
S L
SL
Chirgadze
N Y
NY
Clawson
D K
DK
Denney
M L
ML
Gifford-Moore
D S
DS
Harper
R W
RW
Johnson
L M
LM
Klimkowski
V J
VJ
Kohn
T J
TJ
Lin
H S
HS
McCowan
J R
JR
Richett
M E
ME
Sall
D J
DJ
Smith
A J
AJ
Smith
G F
GF
Snyder
D W
DW
Takeuchi
K
K
Utterback
B G
BG
Yan
S C
SC
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006801:Humans; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013927:Thrombosis / Q000188:drug therapy
D000925:Anticoagulants; D013876:Thiophenes; C088015:benzothiophene; D013917:Thrombin