Design of a potent and orally active nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist
| Autor: | Drake S. Eggleston, Angela S. Wong, Andrew J. Nichols, Chuan-Kui Yuan, R. Curtis Haltiwanger, William E. Bondinell, Paul F. Koster, William H. Miller, Joseph W. Venslavsky, William F. Huffman, Karl F. Erhard, S M Hwang, Janice A. Vasko-Moser, Thomas W. Ku, Chao Pin Lee, Stephen T. Ross, Dalia R. Jakas, Richard M. Keenan, J. Samanen, Richard E. Valocik, Charles W. De Brosse, Fadia E. Ali, Andrew Allen |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
Blood Platelets
Male Stereochemistry Fibrinogen receptor Clinical Biochemistry Molecular Sequence Data Pharmaceutical Science Administration Oral Platelet Membrane Glycoproteins Pharmacology Biochemistry Methylation Peptides Cyclic chemistry.chemical_compound Dogs In vivo Amide Drug Discovery Animals Humans Platelet Amino Acid Sequence Infusions Intravenous Molecular Biology chemistry.chemical_classification Benzodiazepinones Molecular Structure Chemistry Organic Chemistry Antagonist Cyclic peptide Bioavailability Kinetics Molecular Medicine Rabbits Peptides Ex vivo Platelet Aggregation Inhibitors |
| Zdroj: | Bioorganicmedicinal chemistry. 2(9) |
| ISSN: | 0968-0896 |
| Popis: | The direct design of the potent nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist, 8-[[[4- (aminoiminomethyl)phenyl]amino]carbonyl]-2,3,4,5-tetrahydro-3-oxo- 4- (2-phenylethyl)-1H-1,4-benzodiazepine-2-acetic acid, (3) (SB 207448), based on the structure and conformation of the potent and highly constrained cyclic peptide antagonist SKF 107260 (2), has been reported [Ku et al., J. Am. Chem. Soc. 1993, 115, 8861]. While 3 displayed in vivo activity in the conscious dog following intravenous administration, it was not active following intraduodenal administration; activity was measured with an ex vivo platelet aggregation assay. The secondary amide in 3 was N-methylated in the expectation of increased absorption and bioavailability. The resulting tertiary amide, 4 (SB 208651), also showed high binding affinity for human GPIIb/IIIa and potent antiaggregatory activity in human platelet-rich plasma. Most importantly, 4 was active in vivo following intravenous and intraduodenal administration. Comparison of the iv and id inhibition curves suggests an apparent bioavailability of approximately 10%. Thus, 4 represents the first orally active compound in this series of potent, nonpeptide fibrinogen receptor antagonists. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|