Manipulation of kinetic profiles in 2-aryl propionic acid cyclooxygenase inhibitors.
The nonsteroidal anti-inflammatory drugs flurbiprofen and ibuprofen were modified in an attempt to alter the kinetics of inhibitor binding by COX-1. Contrary to prior predictions, a halogen substituent is not sufficient to confer slow tight-binding behavior. Conversion of the carboxylate moiety of flurbiprofen to an ester or amide abolishes slow tight-binding behavior, regardless of halogenation state.
Gupta
Kushol
K
Department of Biochemistry, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
Kaub
Carl J
CJ
Carey
Kristen N
KN
Casillas
Eduard G
EG
Selinsky
Barry S
BS
Loll
Patrick J
PJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002264:Carboxylic Acids / Q000737:chemistry; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005480:Flurbiprofen / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006219:Halogens / Q000737:chemistry; D007052:Ibuprofen / Q000031:analogs & derivatives / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D011422:Propionates / Q000737:chemistry* / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases; D012756:Sheep; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002264:Carboxylic Acids; D016861:Cyclooxygenase Inhibitors; D006219:Halogens; D007527:Isoenzymes; D011422:Propionates; D005480:Flurbiprofen; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C029658:propionic acid; D007052:Ibuprofen