N-(Acyloxyalkyl)pyridinium Salts as Soluble Prodrugs of a Potent Platelet Activating Factor Antagonist
| Autor: | H. R. Heyman, George W. Carter, Steven K. Davidsen, Conway Rg, T. J. Magoc, James B. Summers, James H. Holms, Rhein Da, Daniel H. Albert |
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| Rok vydání: | 1994 |
| Předmět: |
Male
Platelet-activating factor Pyridinium Compounds Chemistry Antagonist Prodrug Pharmacology Chemical synthesis Rats Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Solubility Biochemistry In vivo Drug Discovery Animals Molecular Medicine Prodrugs Pyridinium Platelet Activating Factor |
| Zdroj: | Journal of Medicinal Chemistry. 37:4423-4429 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00052a001 |
| Popis: | Pyrrolothiazole 4 is a potent antagonist of platelet activating factor-mediated effects in a variety of in vitro and in vivo assays. Despite its positive activity in models of inflammation and septic shock, 4 lacks the aqueous solubility necessary for intravenous administration. This deficit was overcome by conversion of 4 to water-soluble pyridinium prodrugs. A two-step procedure was used to prepare a series of N-(acyloxyalkyl)pyridinium salts, all of which exhibited aqueous solubility of greater than 20 mg/mL. The rate of conversion of these prodrugs to 4 was faster in human plasma than in pH 7 aqueous buffer. This rate difference was shown to be due to serum enzymes since the conversion in plasma was significantly slower in the presence of a serine esterase inhibitor. A strong correlation between prodrug structure and buffer/plasma half-life was established. The N-(acetyloxymethyl)pyridinium prodrug 11 (ABT-299) is currently undergoing clinical evaluation for the treatment of sepsis. |
| Databáze: | OpenAIRE |
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