Structure-based design of cyclooxygenase-2 selectivity into ketoprofen.

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Palomer A, Pascual J, Cabre M, Borras L, Gonzalez G, Aparici M, Carabaza A, Cabre F, Garcia ML, Mauleon D

Structure-based design of cyclooxygenase-2 selectivity into ketoprofen.

Bioorg Med Chem Lett. 2002 Feb 25;12(4):533-7.

PubMed ID
11844666 [ View in PubMed
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Abstract

We have recently described how to achieve COX-2 selectivity from the non-selective inhibitor indomethacin (1) using a combination of a pharmacophore and computer 3-D models based on the known X-ray crystal structures of cyclooxygenases. In the present study we have focused on the design of COX-2 selective analogues of the NSAID ketoprofen (2). The design is similarly based on the combined use of the previous pharmacophore together with traditional medicinal chemistry techniques motivated by the comparative modeling of the 3-D structures of 2 docked into the COX active sites. The analysis includes use of the program GRID to detect isoenzyme differences near the active site region and is aimed at suggesting modifications of the basic benzophenone frame of the lead compound 2. The resulting series of compounds bearing this central framework is exemplified by the potent and selective COX-2 inhibitor 17 (LM-1669).

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CelecoxibProstaglandin G/H synthase 2IC 50 (nM)110N/AN/ADetails
KetoprofenProstaglandin G/H synthase 2IC 50 (nM)26N/AN/ADetails
RofecoxibProstaglandin G/H synthase 2IC 50 (nM)830N/AN/ADetails
RofecoxibProstaglandin G/H synthase 2IC 50 (nM)280N/AN/ADetails