Orally Available Soluble Epoxide Hydrolase/Phosphodiesterase 4 Dual Inhibitor Treats Inflammatory Pain

Abstract

Inspired by previously discovered enhanced analgesic efficacy between soluble epoxide hydrolase (sEH) and phosphodiesterase 4 (PDE4) inhibitors, we designed, synthesized and characterized 21 novel sEH/PDE4 dual inhibitors. The best of these displayed good efficacy in in vitro assays. Further pharmacokinetic studies of a subset of four selected compounds led to the identification of a bioavailable dual inhibitor N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA). In a lipopolysaccharide induced inflammatory pain rat model, MPPA rapidly increased in the blood ( T_max = 30 min; C_max = 460 nM) after oral administration of 3 mg/kg and reduced inflammatory pain with rapid onset of action correlating with blood levels over a time course of 4 h. Additionally, MPPA does not alter self-motivated exploration of rats with inflammatory pain or the withdrawal latency in control rats.

Figure 1

MPPA is efficacious against LPS induced inflammatory pain. Baseline thermal withdrawal latencies were determined for each rat before administration of compounds. After baseline determination, MPPA and the vehicle control were administered by oral gavage immediately before a 50 μl intraplantar injection of LPS in saline (arrow) to induce inflammatory pain in male rats. The efficacy of MPPA peaked at 30 min post LPS injection and was largely dissipated by 4 hours. The efficacy at 3 mg/kg was statistically significant compared to vehicle control. Scores are the mean ± SEM reported as percent of baseline (baseline scores normalized to 100%) calculated as the score *100/baseline score (Mann-Whitney Rank Sum Test, T = 448.000 n(small)= 24 n(big)= 36 *p≤0.001, n=6-9/group).

Scheme 1

Development of sEH/PDE4 dual inhibitor design.

Scheme 2

Synthetic routes for the production of sEH/PDE4 dual inhibitors