title: Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists.
abstract: 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.
authors.affiliation: DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0500, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Xue
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: D G
authors.initials: DG
authors.lastname: Batt
authors.forename: G A
authors.initials: GA
authors.lastname: Cain
authors.forename: M
authors.initials: M
authors.lastname: Sworin
authors.forename: A L
authors.initials: AL
authors.lastname: Rockwell
authors.forename: J J
authors.initials: JJ
authors.lastname: Roderick
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: M J
authors.initials: MJ
authors.lastname: Orwat
authors.forename: W E
authors.initials: WE
authors.lastname: Frietze
authors.forename: L L
authors.initials: LL
authors.lastname: Bostrom
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: C A
authors.initials: CA
authors.lastname: Higley
authors.forename: F W
authors.initials: FW
authors.lastname: Rankin
authors.forename: A E
authors.initials: AE
authors.lastname: Tobin
authors.forename: G
authors.initials: G
authors.lastname: Emmett
authors.forename: G K
authors.initials: GK
authors.lastname: Lalka
authors.forename: J Y
authors.initials: JY
authors.lastname: Sze
authors.forename: S V
authors.initials: SV
authors.lastname: Di Meo
authors.forename: S A
authors.initials: SA
authors.lastname: Mousa
authors.forename: M J
authors.initials: MJ
authors.lastname: Thoolen
authors.forename: A L
authors.initials: AL
authors.lastname: Racanelli
authors.forename: R E
authors.initials: RE
authors.lastname: Olson
mesh_terms: 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*
chemical_list: D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C104209:XR 299