Use of conformationally restricted benzamidines as arginine surrogates in the design of platelet GPIIb-IIIa receptor antagonists.
The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional conformational restriction offered by the bicyclic nucleus results in 20-400-fold increases in potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis, structure-activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa antagonists are presented.
Sall
D J
DJ
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Arfsten
A E
AE
Bastian
J A
JA
Denney
M L
ML
Harms
C S
CS
McCowan
J R
JR
Morin
J M
JM
Rose
J W
JW
Scarborough
R M
RM
Smyth
M S
MS
Um
S L
SL
Utterback
B G
BG
Vasileff
R T
RT
Wikel
J H
JH
Wyss
V L
VL
Jakubowski
J A
JA
D001120:Arginine; D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001550:Benzamidines; D007202:Indicators and Reagents; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen; D001120:Arginine