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.
Subject(s)
Isoxazoles/chemical synthesis , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Dogs , Humans , In Vitro Techniques , Injections, Intravenous , Isoxazoles/chemistry , Isoxazoles/metabolism , Isoxazoles/pharmacology , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/metabolism , Platelet Aggregation Inhibitors/pharmacology , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/metabolism , Sulfonamides/pharmacology , Time FactorsABSTRACT
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.
