Structural approaches to explain the selectivity of COX-2 inhibitors: is there a common pharmacophore?
The identification and characterisation of the isoenzyme cyclooxygenase 2 (COX-2) stimulated investigations to develop efficient non-steroidal anti-inflammatory drugs with reduced side effects compared to standard NSAIDs. This review will focus on the structural features needed to achieve COX-2 selectivity. Five structural classes can be identified together with a class bearing little or no resemblance to one another in their molecular structure. The most interesting point is the very distinct structure/activity relationship. On the one hand only minor modifications to a particular compound induce a drastic change in its COX selectivity and on the other hand the structural prerequisites in terms of molecular shape, lipophilicity, electron density, flexibility, polarity and H-bonding dynamics allow a wide range of diversity.
Dannhardt
G
G
Institute of Pharmacy, University of Mainz, Germany. dannhrdt@mail.uni-mainz.de
Laufer
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008565:Membrane Proteins; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011994:Recombinant Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases