Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists |
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Authors: | Kirk D Robarge Michael S Dina Todd C Somers Arthur Lee Thomas E Rawson Alan G Olivero Maureen H Tischler Robert R Webb II Kenneth J Weese Ignacio Aliagas Brent K Blackburn |
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Institution: | Department of Bioorganic Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA |
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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. |
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Keywords: | Tricyclic GPIIb/IIIa antagonists |
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