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  • Title: N-(acyloxyalkyl)pyridinium salts as soluble prodrugs of a potent platelet activating factor antagonist.
    Author: Davidsen SK, Summers JB, Albert DH, Holms JH, Heyman HR, Magoc TJ, Conway RG, Rhein DA, Carter GW.
    Journal: J Med Chem; 1994 Dec 23; 37(26):4423-9. PubMed ID: 7799395.
    Abstract:
    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.
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