Non-Peptide Fibrinogen Receptor Antagonists. 7. Design and Synthesis of a Potent, Orally Active Fibrinogen Receptor Antagonist
| Autor: | M E, Duggan, A M, Naylor-Olsen, J J, Perkins, P S, Anderson, C T, Chang, J J, Cook, R J, Gould, N C, Ihle, G D, Hartman, J J, Lynch |
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| Rok vydání: | 1995 |
| Předmět: |
Magnetic Resonance Spectroscopy
Pan troglodytes Platelet Aggregation Fibrinogen receptor Molecular Sequence Data Administration Oral Peptide Platelet Membrane Glycoproteins Tripeptide Pharmacology Fibrinogen Dogs Piperidines Drug Discovery medicine Animals Humans Platelet Amino Acid Sequence Cells Cultured chemistry.chemical_classification biology Antagonist chemistry Drug Design beta-Alanine biology.protein Molecular Medicine Vitronectin Platelet Aggregation Inhibitors Ex vivo medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 38:3332-3341 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00017a017 |
| Popis: | The design, synthesis, and pharmacological evaluation of L-734,217, a potent, low-molecular weight, orally active fibrinogen receptor antagonist, is reported. A strategy for producing low-molecular weight inhibitors from the peptide c-[(Ac)CRGDC] A, previously reported from these laboratories, is outlined. This strategy combines a retrodesign analysis of the conformationally defined cyclic peptide A with stereochemical information present in the arginine-glycine-aspartic acid (RGD) tripeptide sequence, culminating with the discovery of L-734,217. L-734,217 inhibited the aggregation of human, dog, and chimpanzee platelets at concentrations below 100 nM and was found to be > 15000-fold less effective at inhibiting the attachment of human umbilical vein endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting the aggregation of platelets. L-734,217 showed significant ex vivo antiplatelet activity following oral administration in dogs and chimpanzees at doses of 1.0 and 2.0 mg/kg, respectively, and has been selected as a clinical candidate for development as an antithrombotic agent. |
| Databáze: | OpenAIRE |
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