Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists.
Using isoxazoline XR299 (1a) as a starting point for the design of highly potent, long-duration GPIIb/IIIa antagonists, the effect of placing lipophilic substituents at positions alpha and beta to the carboxylate moiety was evaluated. Of the compounds studied, it was found that the n-butyl carbamate 24u exhibited superior potency and duration of ex vivo antiplatelet effects in dogs. Replacement of the benzamidin-4-yl moiety with alternative basic groups, elimination of the isoxazoline stereocenter, and reversal of the orientation of the isoxazoline ring resulted in lowered potency and/or duration of action.
Xue
C B
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DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0500, USA.
Wityak
J
J
Sielecki
T M
TM
Pinto
D J
DJ
Batt
D G
DG
Cain
G A
GA
Sworin
M
M
Rockwell
A L
AL
Roderick
J J
JJ
Wang
S
S
Orwat
M J
MJ
Frietze
W E
WE
Bostrom
L L
LL
Liu
J
J
Higley
C A
CA
Rankin
F W
FW
Tobin
A E
AE
Emmett
G
G
Lalka
G K
GK
Sze
J Y
JY
Di Meo
S V
SV
Mousa
S A
SA
Thoolen
M J
MJ
Racanelli
A L
AL
Olson
R E
RE
D000284:Administration, Oral; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D005260:Female; D007555:Isoxazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D008956:Models, Chemical; D010215:Papio; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*
D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C104209:XR 299