2.1. Soluble epoxide hydrolase inhibitor

Selective and potent inhibitors (low nanomolar K_i's) for the rodent and human soluble epoxide hydrolase enzyme (sEH) were developed based on the catalytic mechanism and the x‐ray structure of the murine sEH (PDB access #: 1CQZ and 1CR6). ²² , ²³ , ²⁴ The potency, pharmacokinetics, and physiochemical properties of 11 different sEHIs were conducted. 1‐Trifluoromethoxyphenyl‐3‐(1‐propionylpiperidine‐4‐yl)urea (TPPU, containing a piperidine ring) was found to have high inhibitory potency, drug‐like physicochemical properties, pharmacokinetics with high area under the curve values, a relatively longer half‐life and lower plasma protein binding properties than many previous compounds. ²⁵ , ²⁶ For these pharmacokinetic favorable characteristics, TPPU was chosen for this study. TPPU was found to be a low nanomolar inhibitor of the sEH enzyme and was previously tested against commercial drug targets and the NIH screen of drug targets; there were no hits at 10 micromolar (over 1000‐fold higher concentration than the effective concentration for the sEH enzyme). In addition, the x‐ray crystal structure of the sEH enzyme and the inhibitors has been solved. ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ There is no evidence to date of off‐target binding sites.