1-ethyl and 1-propylazacycloalkan-2-one ester prodrugs of ketoprofen. Synthesis, chemical stability, enzymatic hydrolysis, anti-inflammatory activity, and gastrointestinal toxicity.
Six ketoprofen (CAS 22071-15-4) alkylazacycloalkan-2-one ester derivatives (I-VI) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities after oral administration. Furthermore these derivatives were assayed to determine in vitro their stability in pH 7.4 phosphate buffer and in simulated gastric fluid (pH 2.0 buffer) and their susceptibility to enzymatic cleavage in rat plasma. All the prodrugs showed a good stability both in pH 7.4 phosphate buffer and in pH 2.0 buffer, and they were readily hydrolyzed by rat plasma. Esters I-VI showed an anti-inflammatory activity, determined as the percent of inhibition of carrageenan-induced edema, similar to that of ketoprofen, although at higher doses. They were significantly less irritating to the gastric mucosa than the parent drug. In the mouse acetic acid induced writhing assay, the prodrugs exhibited, following acute administration, a good analgesic activity.
Bonina
Francesco Paolo
FP
Department of Pharmaceutical Sciences, School of Pharmacy, University of Catania, Catania, Italy. boninaf@mbox.unict.it
Puglia
Carmelo
C
Ventura
Dario
D
Santagati
Natale Alfredo
NA
Saija
Antonella
A
Trombetta
Domenico
D
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006207:Half-Life; D006868:Hydrolysis; D007202:Indicators and Reagents; D007660:Ketoprofen / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D011355:Prodrugs / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007202:Indicators and Reagents; D011355:Prodrugs; D007660:Ketoprofen