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 inhi bition, XR299 had an IC50 of 0.24 mu M and was a potent antiplatelet a gent when dosed intravenously in a canine model. It was shown through X-ray studies of the cinchonidine salt 49 that the receptor required t he 5(R)-stereochemistry for high potency. The ethyl ester prodrug of X R299, XR300 (29), was orally active in the dog.