Stereoselective cyclooxygenase inhibition in cellular models by the enantiomers of ketoprofen

Abstract

The pharmacological activity of rac-ketoprofen and its enantiomers was investigated in vitro using different cellular models. The effect of these compounds on arachidonic acid metabolism was assessed by measuring the inhibition of prostanoid generation under the action of several agonists. Thus, we have evaluated the inhibition of (1) thromboxane B2 synthesis in rabbit platelets and human polymorphonuclear leukocytes (PMNs), (2) prostaglandin E2 synthesis in three cultured cells, namely human umbilical vein endothelial cells (HUVEC), human keratinocytes, and mouse macrophage-like P388D1 cells. The IC50 values found for (+)-(S)-ketoprofen were in the range between 0.1 nM and 0.8 microM, being slightly lower in all models than those found for rac-ketoprofen (0.4 nM-3 microM). On the other hand (-)-(R)-ketoprofen showed inhibition of cyclooxygenase only at concentrations two or three orders of magnitude higher than those required for the (+)-(S) enantiomer. These results, obtained with cell types of relevance for inflammatory processes and with compounds of high optical purity, demonstrate that the prostanoid biosynthesis inhibition caused by the drug rac-ketoprofen is exclusively due to its dextrorotatory enantiomer.

Fluoroquinolone‐Induced Motor Changes in the Guinea‐Pig Isolated Ileum

“…The excitatory effect of norfloxacin was also inhibited in a concentration-dependent manner by indomethacin and Sketoprofen, two cyclooxygenase inhibitors. The R enantiomer of ketoprofen was ineffective (except at 1 pM), to demonstrate the stereoselectivity and the specificity of the antagonism (Hayball et al 1992;Suesa et al 1993). It is therefore likely that the contractile response to norfloxacin depends on the local production of prostaglandins, which are known to stimulate cholinergic transmission in the myenteric plexus by increasing prejunctional ACh release (Serio & Daniel 1989;Mulholland & Simeone 1993).…”

“…In separate experiments, the contractile effect of norfloxacin was evaluated in the presence of indomethacin, Sketoprofen, or R-ketoprofen (the inactive enantiomer) (Hayball et al 1992;Suesa et al 1993). Indomethacin and S-ketoprofen (both at 0.01-1 pM) concentration-dependently reduced norfioxacin-induced contractions, and completely abolished them at 1 pM.…”

Spin effects in intramolecular electron transfer in naproxen-N-methylpyrrolidine dyad

“…This interest is inspired by the importance of optical isomers for the different scientific areas, i.e., from the problems connected with the origin of life on the Earth, to the pharmacological problems of the varying remedial activity of drug enantiomers [1,2,3].…”

Spin Chemistry Investigation of Peculiarities of Photoinduced Electron Transfer in Donor–Acceptor Linked System

“…Less is known about steric factors, in particular, the effect of chiral centers present in the donor or acceptor molecular fragments. Meanwhile, the chiral systems attract special attention in recent years because of the importance of optical isomers for different areas of science, from the origin of life to pharmacological problems related to different activity of drug enantiomers [5][6][7].…”