Fused bicyclic Gly-Asp beta-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere.
6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.
Fisher
M J
MJ
Eli Lilly and Company, Indianapolis, Indiana 46028, USA.
Giese
U
U
Harms
C S
CS
Kinnick
M D
MD
Lindstrom
T D
TD
McCowan
J R
JR
Mest
H J
HJ
Morin
J M
JM
Mullaney
J T
JT
Paal
M
M
Rapp
A
A
Rühter
G
G
Ruterbories
K J
KJ
Sall
D J
DJ
Scarborough
R M
RM
Schotten
T
T
Stenzel
W
W
Towner
R D
RD
Um
S L
SL
Utterback
B G
BG
Wyss
V L
VL
Jakubowski
J A
JA
D000085:Acetates / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000578:Amidines / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000737:chemistry; D001550:Benzamidines / Q000737:chemistry; D001682:Biological Availability; D004341:Drug Evaluation; D004797:Enzyme-Linked Immunosorbent Assay; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D051381:Rats; D013237:Stereoisomerism; D044024:Tetralones
C407727:6-((4-amidinobenzoyl)amino)tetralone-2-acetic acid; D000085:Acetates; D000578:Amidines; D001550:Benzamidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011355:Prodrugs; D044024:Tetralones; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D001120:Arginine; C032157:benzamidine