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

• Published in: Journal of medicinal chemistry Vol. 37; no. 26; pp. 4423 - 4429
• Main Authors: Davidsen, Steven K, Summers, James B, Albert, Daniel H, Holms, James H, Heyman, H. Robin, Magoc, Terrance J, Conway, Richard G, Rhein, David A, Carter, George W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-12-1994
• Subjects: Animals; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Male; Medical sciences; Pharmacology. Drug treatments; Platelet Activating Factor - antagonists & inhibitors; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Pyridinium Compounds - chemical synthesis; Pyridinium Compounds - pharmacology; Rats; Rats, Sprague-Dawley; Solubility; Structure-Activity Relationship; Organic cation; Rat; Iminium compounds; Rodentia; Prodrug; In vitro; Antiplatelet agent; In vivo; Vertebrata; Mammalia; Structure activity relation; Animal; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• 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.