Discovery of dual target inhibitors against cyclooxygenases and leukotriene A4 hydrolyase.

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Chen Z, Wu Y, Liu Y, Yang S, Chen Y, Lai L

Discovery of dual target inhibitors against cyclooxygenases and leukotriene A4 hydrolyase.

J Med Chem. 2011 May 26;54(10):3650-60. doi: 10.1021/jm200063s. Epub 2011 May 4.

PubMed ID

21542630 [ View in PubMed

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Abstract

Dual target inhibitors against COX-2 and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activities using enzyme assays and human whole blood assay. Introduction of small electron withdrawing groups like NO(2) and CF(3) in the ortho-position of the terminal phenyl ring was found to change the original single target LTA(4)H inhibitor to dual target LTA(4)H and COX-2 inhibitors. Compound 5a and 5m showed dual LTA(4)H and COX-2 inhibition activities in the enzyme assays and the HWB assay with IC(50) values in the micromolar to submicromolar range. As their activities in HWB assay were comparable to the two starting single target inhibitors, the two compounds are promising for further studies. The strategy used in the current study may be generally applicable to other dual target drug designs.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Nimesulide	Prostaglandin G/H synthase 2	IC 50 (nM)	8700	N/A	N/A	Details
Nimesulide	Prostaglandin G/H synthase 2	IC 50 (nM)	23	N/A	N/A	Details