title: Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action.
abstract: Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.
authors: The DuPont Merck Pharmaceutical Company, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
authors: R E
authors: RE
authors: Olson
authors: T M
authors: TM
authors: Sielecki
authors: J
authors: J
authors: Wityak
authors: D J
authors: DJ
authors: Pinto
authors: D G
authors: DG
authors: Batt
authors: W E
authors: WE
authors: Frietze
authors: J
authors: J
authors: Liu
authors: A E
authors: AE
authors: Tobin
authors: M J
authors: MJ
authors: Orwat
authors: S V
authors: SV
authors: Di Meo
authors: G C
authors: GC
authors: Houghton
authors: G K
authors: GK
authors: Lalka
authors: S A
authors: SA
authors: Mousa
authors: A L
authors: AL
authors: Racanelli
authors: E A
authors: EA
authors: Hausner
authors: R P
authors: RP
authors: Kapil
authors: S R
authors: SR
authors: Rabel
authors: M J
authors: MJ
authors: Thoolen
authors: T M
authors: TM
authors: Reilly
authors: P S
authors: PS
authors: Anderson
authors: R R
authors: RR
authors: Wexler
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors
chemical_list: C114713:DMP 802; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013449:Sulfonamides