title: Discovery of potent isoxazoline glycoprotein IIb/IIIa receptor antagonists.
abstract: 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.
authors.affiliation: DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0500, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wityak
authors.forename: T M
authors.initials: TM
authors.lastname: Sielecki
authors.forename: D J
authors.initials: DJ
authors.lastname: Pinto
authors.forename: G
authors.initials: G
authors.lastname: Emmett
authors.forename: J Y
authors.initials: JY
authors.lastname: Sze
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: A E
authors.initials: AE
authors.lastname: Tobin
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Jiang
authors.forename: P
authors.initials: P
authors.lastname: Ma
authors.forename: S A
authors.initials: SA
authors.lastname: Mousa
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
authors.forename: R E
authors.initials: RE
authors.lastname: Olson
mesh_terms: 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
chemical_list: D007555:Isoxazoles; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C104209:XR 299