N-(ACYLOXYALKYL)PYRIDINIUM SALTS AS SOLUBLE PRODRUGS OF A POTENT PLATELET-ACTIVATING-FACTOR ANTAGONIST

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 l acks the aqueous solubility necessary for intravenous administration. This deficit was overcome by conversion of 4 to water-soluble pyridini um prodrugs. A two-step procedure was used to prepare a series of N-(a cyloxyalkyl)pyridinium salts, all of which exhibited aqueous solubilit y of greater than 20 mg/mL. The rate of conversion of these prodrugs t o 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 i n 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 pr odrug 11 (ABT-299) is currently undergoing clinical evaluation for the treatment of sepsis.