Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists
| Autor: | Rob Webb, Kirk Robarge, Dina Michael S, Weese Kenneth J, Alan G. Olivero, Todd C. Somers, Brent Blackburn, Ignacio Aliagas, Maureen H. Tischler, Thomas E. Rawson, Arthur Lee |
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| Rok vydání: | 1999 |
| Předmět: |
Models
Molecular congenital hereditary and neonatal diseases and abnormalities Platelet Aggregation Stereochemistry Clinical Biochemistry Molecular Conformation Pharmaceutical Science Platelet Glycoprotein GPIIb-IIIa Complex Pharmacology Biochemistry Benzodiazepines Structure-Activity Relationship Fibrinolytic Agents hemic and lymphatic diseases Drug Discovery Structure–activity relationship Humans Molecular Biology chemistry.chemical_classification Benzodiazepinones Bicyclic molecule Molecular Structure Chemistry Organic Chemistry Fibrinogen binding Biological activity Molecular Medicine Platelet aggregation inhibitor Indicators and Reagents Fibrinolytic agent Platelet Aggregation Inhibitors circulatory and respiratory physiology Tricyclic |
| Zdroj: | Bioorganicmedicinal chemistry. 6(12) |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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