Antithrombotic Drugs-the Activity And Synthesis Of The Glycoprotein â…¡b/â…¢a Antagonists

The thrombus formation is one of the causes of the cardiovascular diseases, in which process platelet aggregation involves the central event mediated by the binding of the plasma protein fibrinogen to the glycoprotein IIb/IIIa receptor (GPIIb/IIIa) on the surface of activated platelet. This binding is final common pathway for platelet aggregation. Therefore GPIIb/IIIa antagonists can completely inhibit platelet aggregation regardless of the various agonist(collagen, thrombin et al) involved. So GPIIb/IIIa receptor antagonists have a huge market value.Two series of compounds with amidinophenyl and carbonyl groups were synthesized in this dissertation:(1)linear compounds: the two pharmacophores being separated by a linear skeleton; (2)benzodiazepine compounds: the pharmacophores being attached on the benzodiazepine scaffold. (1)linear compoundsBefore design and synthesis of me-too compounds of existing GPIIb/IIIa antagonists, a 3D-QSAR analysis was conducted with 16 reported compounds using CoMFA. The result indicated both steric and electrostatic fields affect the inhibitory activity.Based on 3-D QSAR model and me-too drug design principle, the new compounds with proprietary were designed and synthesized through the change of the side chains of amino acids of Sibrafiban and Lamifiban which were investigated in clinical phase III and used as model compounds. Among the synthesized target compounds, GPI-3, GPI-4, GPI-8, GPI-9, GPI-12, GPI-13, GPI-15, GPI-22 and GPI-23 showed the activities as potent as the model compounds. And GPI-3, GPI-4, GPI-12, GPI-13 were further assayed in vivo. The result demonstrated these compounds maintained the metabolic stability and inhibited platelet aggregation in high level with a prolonged duration of activity, superior to the model compounds. The further experiments were being carried on.(2) benzodiazepine compoundsThe benzodiazepine compounds were designed and synthesized by using Lotrafiban as lead compound. The biological assays are in test.In this dissertation, 120 compounds were synthesized, in which 71 compounds were novel and 36 compounds is the target molecules and identified.