1. Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists.
- Author
-
Robarge KD, Dina MS, Somers TC, Lee A, Rawson TE, Olivero AG, Tischler MH, Webb RR 2nd, Weese KJ, Aliagas I, and Blackburn BK
- Subjects
- Benzodiazepines chemistry, Benzodiazepines pharmacology, Benzodiazepinones chemistry, Benzodiazepinones pharmacology, Fibrinolytic Agents chemistry, Fibrinolytic Agents pharmacology, Humans, Indicators and Reagents, Models, Molecular, Molecular Conformation, Molecular Structure, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors chemistry, Platelet Aggregation Inhibitors pharmacology, Structure-Activity Relationship, Benzodiazepines chemical synthesis, Benzodiazepinones chemical synthesis, Fibrinolytic Agents chemical synthesis, Platelet Aggregation Inhibitors chemical synthesis, Platelet Glycoprotein GPIIb-IIIa Complex antagonists & inhibitors
- Abstract
Antagonists of the glycoprotein GPIIb/IIIa are a promising class of antithrombotic agents offering potential advantages over present antiplatelet agents (i.e., aspirin and ticlopidine). Novel tricyclic nonpeptidal GPIIb/IIIa antagonists have been prepared and evaluated in vitro as antagonists of fibrinogen binding to the purified GPIIb/IIIa receptor and as inhibitors of platelet aggregation. The work presented demonstrates the robustness of the benzodiazepinedione (BZDD) scaffold, which can be functionalized at the N1-C2 amide as well as at C7, to provide structural diversity and allow optimization of the physiochemical and pharmacological properties of the BZDD based GPIIb/IIIa antagonists. In addition, the resulting new class of tricyclic GPIIb/IIIa antagonists could be used to probe for additional binding interactions on the GPIIb/IIIa receptor and perhaps lead to BZDD based GPIIb/IIIa antagonists with increased potency. The tricyclic molecules reported herein demonstrate that a heterocyclic ring can be fused to the benzodiazepinedione scaffold with retention of anti-aggregatory potency and in the case of tetrazole 30i, increased potency relative to the bicyclic analogue 1c.
- Published
- 1998
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