Structure-based pharmacophore of COX-2 selective inhibitors and identification of original lead compounds from 3D database searching method.

A four-point pharmacophore of COX-2 selective inhibitors was derived from a training set of 16 compounds, using the Catalyst program. It consists of a H bond acceptor, two hydrophobic groups and an aromatic ring, in accordance with SAR data of the compounds and with topology of the COX-2 active site. This hypothesis, combined with exclusion volume spheres representing important residues of the COX-2 binding site, was used to virtually screen the Maybridge database.

The use of nimesulide and its analogues in cancer chemoprevention.

Non-steroidal anti-inflammatory drugs (NSAIDs), which are known to be cyclooxygenase (COX) inhibitors, have been reported to exert anti-proliferative and pro-apoptotic effects on a variety of cancer cells. Since the COX-2 isoform was found to be overexpressed in a many human cancers, a particular attention was paid on the possible use of selective COX-2 inhibitors in cancer chemoprevention. The present review focuses on the state of the art in cancer research developed with COX-2 preferential/selective inhibitors belonging to the family of N-arylmethanesulfonamides, in particular nimesulide and NS-398.

A new potential cyclooxygenase-2 inhibitor, pyridinic analogue of nimesulide.

In this paper, the binding mode of original pyridinic compounds structurally related to nimesulide, a preferential cyclooxygenase (COX)-2 inhibitor, is analyzed by docking simulations in order to understand structure-activity relationships of this family. Structural modifications are proposed to reverse the selectivity of the more active inhibitor of the series characterized by a preferential activity on COX-1. On the basis of these modifications, a new compound with a bromo substituent was designed and showed a COX-2 selective inhibition.

Synthesis, molecular modelling and enzymatic evaluation of (+/-)3,5-diphenyl-2-thioxoimidazolidin-4-ones as new potential cyclooxygenase inhibitors.

A series of substituted (+/-)3,5-diphenyl-2-thioxoimidazolin-4-ones was synthesized in order to design new type-2 cyclooxygenase (COX-2) inhibitors. This study has led to molecules which completely inhibit human recombinant COX-2 at 50 microM. Molecular modelling highlighted drug interactions with the active site of both cyclooxygenases and suggested modifications to enhance the selectivity of the compounds.

Design, synthesis, and pharmacological evaluation of pyridinic analogues of nimesulide as cyclooxygenase-2 selective inhibitors.

In this study, we report the synthesis and pharmacological evaluation of original pyridinic sulfonamides related to nimesulide, a cyclooxygenase-2 (COX-2) preferential inhibitor widely used as an anti-inflammatory agent. These original pyridinic derivatives were synthesized in three steps starting from the condensation of 3-bromo-4-nitropyridine N-oxide with appropriately substituted phenols, thiophenols, or anilines followed by a reduction of the nitro moiety into the corresponding aminopyridine, which was finally condensed with alkane- or trifluoromethanesulfonyl chloride to obtain the corresponding sulfonamides. The pK(a) determinations demonstrated that the major ionic form present in solution at physiological pH depends on the nature of the sulfonamide moiety subsituent.