1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain

Abstract

1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in C(max), and a 3300-fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea (2). This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.

Figure 1

The soluble epoxide hydrolase inhibitor 52 (sEHi) reduces local inflammatory pain at a far lower dose than morphine. The inflammatory agent carrageenan was administered at time 0 resulting in a stable hyperalgesic response for the duration of the experiment. Zero time points represent normal response to pain. Treatment at 180 minutes post carrageenan with either morphine or compound 52 reversed symptoms. Standard deviation represents the average of 6 animals with regard to mechanical withdrawal threshold.

Scheme 1

Synthesis of N-propionyl piperidine analogues Reaction conditions: (a) triphosgene, DCM, sat. NaHCO₃ or 1N NaOH, sat. NaCl, 0 °C, 10min; (b) 4-nitrophenyl chloroformate, Et₃N, THF, 0 to 50 °C, 1-3h; (c) 1, THF, 0 °C to rt, 1-24h; (d) 1, DMF, 70 °C, 4h.

Scheme 2

Synthesis of N-acyl and N-sulfonyl piperidine analogues Reagents and conditions: (a) 1-BOC-4-aminopiperidine, THF, 0 °C to rt, 12h; (b) 1N HCl in MeOH, reflux, 3h; (c) R¹SO₂Cl, Et₃N, THF, 0 °C to rt, 12h; (d) EDCI, R²COOH, DMAP, DCM, rt, 12-24h.