Discovery of potent isoxazoline glycoprotein IIb/IIIa receptor antagonists.
Using the isoxazoline as a common structural feature, three series of glycoprotein IIb/IIIa receptor antagonists were evaluated, culminating in the discovery of XR299 (30). In an in vitro assay of platelet inhibition, XR299 had an IC50 of 0.24 microM and was a potent antiplatelet agent when dosed intravenously in a canine model. It was shown through X-ray studies of the cinchonidine salt 49 that the receptor required the 5(R)-stereochemistry for high potency. The ethyl ester prodrug of XR299, XR300 (29), was orally active in the dog.
Wityak
J
J
DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0500, USA.
Sielecki
T M
TM
Pinto
D J
DJ
Emmett
G
G
Sze
J Y
JY
Liu
J
J
Tobin
A E
AE
Wang
S
S
Jiang
B
B
Ma
P
P
Mousa
S A
SA
Wexler
R R
RR
Olson
R E
RE
D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011487:Protein Conformation
D007555:Isoxazoles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C104209:XR 299