Soluble epoxide hydrolase inhibitors

Flwang, S.H., et al. Orally bioavailable potent soluble epoxide hydrolase inhibitors. J. Med. Chem. 2007, 50, 3825-3840. 

Aminoheterocycle bioisosteric approaches to amide groupings are exemplified in a report on soluble epoxide hydrolase inhibitors [5j. The replacement of the amide grouping in 1 by adoption of the tethering strategy of linking the carbonyl to adjacent side chains or benzene rings produced 2 (Figure 3.2). 

Mayer, R.J., Booth-Genthe, C.L., and CaUahan, J.F. (2013) In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor. 

A specific example of prudent hit-to-lead design is illustrated in the development of soluble epoxide hydrolase inhibitors by Tanaka et al. [16]. By placing more emphasis on ligand efficiency of hits rather than the better absolute potency of larger and more lipophilic hits, they explored the SAR of the cyclopropyl amide shown in Figure 17.5. While the hit compound has only 0.5 micromolar activity, it has quite good ligand efficiency and is amenable to rapid... 

Figure 17.5 An example of selecting and expanding SAR around a soluble epoxide hydrolase Inhibitor hit compound (top) containing a core with a high ligand efficiency. Although It had weaker potency (565 nM), other more potent hits ( 10nM, structures undisclosed) were more lipophilic and not as...

Tanaka, D., Tsuda, Y., Shiyama, T., Nishimura, T., Chiyo, N., Tominaga, Y., Sawada, N., Mimoto, T., and Kusunose, N. (2011) A practical use of ligand efficiency indices out of the fragment-based approach ligand efficiency-guided lead identification of soluble epoxide hydrolase inhibitors. Journal of Medicinal Chemistry, 54, 851-857. 

Hydroxy amides and keto amides as a primary pharmacophore in soluble epoxide hydrolase inhibitors... 

C. Morisseau, G. Du, J. W. Newman, B. D. Hammock, Mechanism of Mammalian Soluble Epoxide Hydrolase by Chalcone Oxide Derivatives , Arch. Biochem. Biophys. 1998, 356, 214 - 228 C. Morisseau, M. H. Goodrow, D. Dowdy, J. Zheng, J. F. Greene, J. R. Sanborn, B. D. Hammock, Potent Urea and Carbamate Inhibitors of Soluble Epoxide Hydrolases , Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 8849 - 8854. 

Figure 1 Building an active site model of the human soluble epoxide hydrolase, (a) X-ray crystal structure with the active site highlighted (PDB 1VJ5) (b) Important active site residues, a water molecule, and the CIU inhibitor, are extracted from the PDB file (c) Final quantum chemical model of the sEH active site. Residues are truncated so that in principle only important side chains and backbone parts were included in the model. The substrate MSO is modeled instead of the inhibitor. Asterisks indicate atoms that were kept fixed to their crystallographically observed positions.

An example illustrating the beneficial effect including protein structure information in the library design process is presented. Xing et al published the discovery of soluble epoxide hydrolase (sEH) inhibitors [7]. The binding mode of a benzoxazole compound in complex with sEH was determined. The potent... 

R.E. (2013) Discovery of 1-(1 3,5-triazin-2-yl) piperidine-4-carboxamides as inhibitors of soluble epoxide hydrolase. Bioorganic and Medicinal Chemistry Letters, 23,3584-3588. 

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