Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A4Hydrolyase

Dual target inhibitors against COX-2 and LTA4H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA4H 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 NO2and CF3in the ortho-position of the terminal phenyl ring was found to change the original single target LTA4H inhibitor to dual target LTA4H and COX-2 inhibitors. Compound 5aand 5mshowed dual LTA4H and COX-2 inhibition activities in the enzyme assays and the HWB assay with IC50values 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.