title: N-(acyloxyalkyl)pyridinium salts as soluble prodrugs of a potent platelet activating factor antagonist.
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.
authors.affiliation: Immunosciences Research Area, Department 47J, Abbott Laboratories, Abbott Park, Illinois 60064.
authors.forename: S K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: J B
authors.initials: JB
authors.lastname: Summers
authors.forename: D H
authors.initials: DH
authors.lastname: Albert
authors.forename: J H
authors.initials: JH
authors.lastname: Holms
authors.forename: H R
authors.initials: HR
authors.lastname: Heyman
authors.forename: T J
authors.initials: TJ
authors.lastname: Magoc
authors.forename: R G
authors.initials: RG
authors.lastname: Conway
authors.forename: D A
authors.initials: DA
authors.lastname: Rhein
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
mesh_terms: D000818:Animals; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D010972:Platelet Activating Factor; D011355:Prodrugs; D011726:Pyridinium Compounds