Design and synthesis of novel platelet fibrinogen receptor antagonists with 2H-1,4-benzoxazine-3(4H)-one scaffold. A systematic study.
New platelet glycoprotein IIb/IIIa (GP IIb/IIIa, integrin alpha(IIb)beta3) antagonists were prepared on a 2H-1,4-benzoxazine-3(4H)-one scaffold. Their anti-aggregatory activities in human platelet rich plasma and their affinity towards alpha(IIb)beta3 and alpha(V)beta3 integrins were assessed. Various substitution positions and side chain variations were studied. In contrast to the generally accepted model, compounds containing ethyl esters as aspartate mimetics were in general more active than the corresponding free acids. We suggest an explanation for the observed behaviour of these new compounds.
Anderluh
Marko
M
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
Cesar
Jozko
J
Stefanic
Petra
P
Kikelj
Danijel
D
Janes
Damjan
D
Murn
Jernej
J
Nadrah
Kristina
K
Tominc
Mojca
M
Addicks
Elisabeth
E
Giannis
Athanassios
A
Stegnar
Mojca
M
Dolenc
Marija Sollner
MS
D001224:Aspartic Acid; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D001792:Blood Platelets / Q000737:chemistry / Q000187:drug effects*; D015195:Drug Design; D039302:Integrin alphaVbeta3; D018716:Molecular Mimicry; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D039341:Receptors, Fibrinogen / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D048588:Benzoxazines; D039302:Integrin alphaVbeta3; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D039341:Receptors, Fibrinogen; D001224:Aspartic Acid