N-(Acyloxyalkyl)pyridinium Salts as Soluble Prodrugs of a Potent Platelet Activating Factor Antagonist

Article abstract of DOI:10.1021/jm00052a001

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.