Design, synthesis, and biological evaluation of ketoprofen analogs as potent cyclooxygenase-2 inhibitors.
A new series of ketoprofen analogs were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that all compounds were potent and selective inhibitors of the COX-2 isozyme with IC(50) values in the highly potent 0.057-0.085 microM range, and COX-2 selectivity indexes in the 115 to >1298.7 range. Compounds possessing azido pharmacophore group (8a and 8b) exhibited highly COX-2 inhibitory selectivity and potency even more than reference drug celecoxib. Molecular modeling studies indicated that the azido substituent can be inserted deeply into the secondary pocket of COX-2 active site for interactions with Arg(513).
Zarghi
Afshin
A
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. azarghi@yahoo.com
Ghodsi
Razieh
R
D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007660:Ketoprofen / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D012756:Sheep; D013329:Structure-Activity Relationship
D052246:Cyclooxygenase 2 Inhibitors; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2