Structural highlights
Function
[HYES_HUMAN] Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides. Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid, 12-phosphonooxy-octadec-9E-enoic acid, and p-nitrophenyl phospate.[1] [2]
Publication Abstract from PubMed
Multi-target inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH. Inhibitors with a 6-fold increase of FAAH potency while maintaining high sEH potency were developed by optimization. Interestingly, compared to most FAAH inhibitors that inhibit through time-dependent covalent modification, t-TUCB and related compounds appear to inhibit FAAH through a time-independent, competitive mechanism. These inhibitors are selective for FAAH over other serine hydrolases. In addition, FAAH inhibition by t-TUCB appears to be higher in human FAAH over other species; however, the new dual sEH/FAAH inhibitors have improved cross-species potency. These dual inhibitors may be useful for future studies in understanding the therapeutic application of dual sEH/FAAH inhibition.
Identification and optimization of soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase.,Kodani SD, Bhakta S, Hwang SH, Pakhomova S, Newcomer ME, Morisseau C, Hammock BD Bioorg Med Chem Lett. 2018 Jan 4. pii: S0960-894X(18)30003-9. doi:, 10.1016/j.bmcl.2018.01.003. PMID:29366648[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cronin A, Mowbray S, Durk H, Homburg S, Fleming I, Fisslthaler B, Oesch F, Arand M. The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1552-7. Epub 2003 Feb 6. PMID:12574508 doi:10.1073/pnas.0437829100
- ↑ Newman JW, Morisseau C, Harris TR, Hammock BD. The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1558-63. Epub 2003 Feb 6. PMID:12574510 doi:10.1073/pnas.0437724100
- ↑ Kodani SD, Bhakta S, Hwang SH, Pakhomova S, Newcomer ME, Morisseau C, Hammock BD. Identification and optimization of soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase. Bioorg Med Chem Lett. 2018 Jan 4. pii: S0960-894X(18)30003-9. doi:, 10.1016/j.bmcl.2018.01.003. PMID:29366648 doi:http://dx.doi.org/10.1016/j.bmcl.2018.01.003
