Submitted to: Bioorganic and Medicinal Chemistry
Publication Type: Peer reviewed journal
Publication Acceptance Date: 7/14/2006
Publication Date: 7/17/2006
Citation: Norisseau, C., Newman, J.W., Tsai, H., Baecker, P.A., Hammock, B.D. Peptidyl-urea based inhibitors of soluble epoxide hydrolases. 2006. Bioorganic and Medicinal Chemistry Letters. Vol.16: 5439-5444. Interpretive Summary: A combinatorial chemistry approach was used to prepare a series of amino acid derived cyclohexyl and adamantyl ureas, and the utility of these compounds as soluble epoxide hydrolase inhibitors was explored. Therapeutic inhibition of this enzyme may have benefits in a number of human disorders including hypertension and inflammation. Potent, structurally distinct inhibitors of both the mouse and human enzymes were discovered. While these compounds showed low inherent bioavailability, they documented that the targeted enzyme itself can accept larger polar side-chains than previously thought. Therefore, these findings offer new insights which may lead to better orally available drugs.
Technical Abstract: We prepared a series of amino acid derived cyclohexyl and adamantyl ureas and tested them as inhibitors of the human soluble epoxide hydrolase, and obtained very potent compounds (K(I)=15nM) that are >10-fold more soluble than previously described sEH inhibitors. While our lead compound 2 showed low apparent bioavailability in dogs and rats, this series of compounds revealed that sEH inhibitor structures could accept large groups that could lead to better orally available drugs.