Orally Active Isoxazoline Glycoprotein IIb/IIIa Antagonists with Extended Duration of Action

• Published in: Journal of medicinal chemistry Vol. 42; no. 7; pp. 1178 - 1192
• Main Authors: Olson, Richard E, Sielecki, Thais M, Wityak, John, Pinto, Donald J, Batt, Douglas G, Frietze, William E, Liu, Jie, Tobin, A. Ewa, Orwat, Michael J, Di Meo, Susan V, Houghton, Gregory C, Lalka, George K, Mousa, Shaker A, Racanelli, Adrienne L, Hausner, Elizabeth A, Kapil, Ram P, Rabel, Shelley R, Thoolen, Martin J, Reilly, Thomas M, Anderson, Paul S, Wexler, Ruth R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.04.1999; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Chemistry, Medicinal; Crystallography, X-Ray; Dogs; Humans; In Vitro Techniques; Injections, Intravenous; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - metabolism; Isoxazoles - pharmacology; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - metabolism; Platelet Aggregation Inhibitors - pharmacology; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - metabolism; Sulfonamides - pharmacology; Time Factors; CORONARY-ARTERY DISEASE; IN-VITRO ACTIVITIES; PLATELET-AGGREGATION; ASPARTIC-ACID; ALPHA-SULFONAMIDES; ANTIPLATELET EFFICACY; POTENT INHIBITORS; BINDING AFFINITY; FIBRINOGEN; GPIIB/IIIA RECEPTOR ANTAGONIST; Intravenous administration; Isoxazole derivatives; Anticoagulant; Ex vivo; Structure activity relation; Fibrinogen; Antagonist; Chemical synthesis; Dog; Oxygen nitrogen heterocycle; Biological receptor; Human; Fissipedia; Carnivora; Glycoprotein IIbIIIa; Sulfonamide; Benzene derivatives; Oral administration; In vitro; Antiplatelet agent; α-Aminoacid; Vertebrata; Amidine; Mammalia; Bolus injection; Animal; Affinity; Pharmacokinetics; Duration of action
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980348t

Modification of the α-carbamate substituent of isoxazoline GPIIb/IIIa (αIIbβ3) antagonist DMP 754 (7) led to a series of α-sulfonamide and α-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-α-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.