Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa.
Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent leads for further structural evaluation. Structure-activity studies centered on the bicyclic beta-turn mimic contained in these molecules indicated that this moiety could accommodate a variety of modifications. Specifically, monocyclic, 6, 5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to the supporting nucleus can be accomplished with an ether or amide linkage, although the latter enhances activity. Several compounds in this series provided measurable blood levels after oral dosing. Conversion of the acid moiety in these molecules to an ester generally provided compounds which gave greater systemic exposure after oral administration. Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.
Fisher
M J
MJ
Eli Lilly and Company, Indianapolis, Indiana 46028, Lilly Research Laboratories, Hamburg, Germany, and COR Therapeutics, Inc., South San Francisco, California 94080, USA.
Arfstan
A E
AE
Giese
U
U
Gunn
B P
BP
Harms
C S
CS
Khau
V
V
Kinnick
M D
MD
Lindstrom
T D
TD
Martinelli
M J
MJ
Mest
H J
HJ
Mohr
M
M
Morin
J M
JM
Mullaney
J T
JT
Nunes
A
A
Paal
M
M
Rapp
A
A
Rühter
G
G
Ruterbories
K J
KJ
Sall
D J
DJ
Scarborough
R M
RM
Schotten
T
T
Sommer
B
B
Stenzel
W
W
Towner
R D
RD
Um
S L
SL
D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001682:Biological Availability; D004797:Enzyme-Linked Immunosorbent Assay; D006168:Guinea Pigs; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry*; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017433:Protein Structure, Secondary; D051381:Rats; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D001578:Benzopyrans; D007546:Isoquinolines; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013764:Tetrahydronaphthalenes