celecoxib and on the other hand we designed and tested a series of dual sEH/COX-2 inhibitors. The resulting dual sEH/COX-2 inhibitor is similarly potent compared to rofecoxib although less potent than celecoxib and has low nM inhibitory potency on recombinant sEH enzyme in vitro [59]. As expected from earlier work, co-administration of a low dose of sEH inhibitor with a low dose of celecoxib was highly effective in reducing pain-related behavior in a rat model of inflammatory pain (Figure 2) [59]. This is in agreement with results from the LPS induced mouse model of sepsis where co-administration of a sEHI with various COX inhibitors was synergistically anti-inflammatory [55]. However we were surprised to find that the dual sEH/COX-2 inhibitor was not only very effective but far exceeded the efficacy of either inhibitor alone or the independent larger dose co-administration of sEH inhibitor with celecoxib. A designed multiple ligand (DML) inhibitor has several advantages compared to combined therapies. These include synergistically increased bioactivity, an increased margin of safety, predictability and straightforwardness of pharmacokinetics and pharmacodynamics and ease of formulation. In the case of the sEH/COX-2 inhibitor additional advantages include reduction of side effects of COX inhibitors such as disturbance of prostacyclin
