Analogs of platelet activating factor. 8. Antagonists of PAF containing an aromatic ring linked to a pyridinium ring
| Autor: | Michael P. Trova, Suresh S. Kerwar, Walter C. Pickett, Constance Kohler, Robert E. Schaub, Allan Wissner, Lawrence Wayne Torley, Marion L. Carroll |
|---|---|
| Rok vydání: | 1993 |
| Předmět: |
Platelet Aggregation
medicine.drug_class Stereochemistry Pyridinium Compounds Carboxamide Imides Mice Structure-Activity Relationship chemistry.chemical_compound In vivo Amide Drug Discovery medicine Animals Platelet Activating Factor Imide Molecular Structure Platelet-activating factor Antagonist Biological activity Amides chemistry Molecular Medicine lipids (amino acids peptides and proteins) Carbamates Rabbits Pyridinium |
| Zdroj: | Journal of Medicinal Chemistry. 36:580-590 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00057a008 |
| Popis: | A series of platelet activating factor (PAF) antagonists containing a quaternary pyridinium ring connected through an amide, imide, or carbamate linkage to a substituted aromatic ring was prepared. Of these compounds, those containing a branched imide linkage of the form (CON-(COCH3)CH2, 37-51, and 59) generally showed excellent PAF antagonist properties in vitro. Structure-activity relationships within this series of compounds were studied extensively with respect to substituents and the position of substitution in both the aromatic and pyridinium rings. Several of these compounds (40 and 44) showed in vitro PAF antagonism at less than 0.1 microM and are as potent as CV-6209, the most potent PAF antagonist reported in the literature. Less active PAF antagonists were those bearing simple amide linkages (20-23, 27-29, and 31-35), linear imide linkages (62-63), or carbamate linkages (66 and 68), between the two aromatic rings. A number of our PAF antagonists were tested in vivo in mice and rabbits for their ability to protect these animals against a lethal injection of PAF. Those antagonists that are particularly potent (IC50 < 0.1 microM) provide excellent protection against an LD97 dose of PAF in rabbits. The relationships between structure and activity in vitro and in vivo are presented and compared to literature standards. |
| Databáze: | OpenAIRE |
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