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 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.
Davidsen
S K
SK
Immunosciences Research Area, Department 47J, Abbott Laboratories, Abbott Park, Illinois 60064.
Summers
J B
JB
Albert
D H
DH
Holms
J H
JH
Heyman
H R
HR
Magoc
T J
TJ
Conway
R G
RG
Rhein
D A
DA
Carter
G W
GW
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
D010972:Platelet Activating Factor; D011355:Prodrugs; D011726:Pyridinium Compounds