Soluble epoxide hydrolase inhibitors with carboranes as non-natural 3-D pharmacophores

Abstract

In the present article we describe the creation of a small carboranylcarboxamide compound library followed by a screening campaign at the soluble epoxide hydrolase (sEH). We identified meta-carboranyl alkylamides, -anilides, and -benzylamides as potent sEH inhibitors. Furthermore, we optimized the scaffolds and we derived structure-activity relationships. The most potent benzylamide 33 (MS1) was similar to a previously reported adamantane derivative and gave an IC₅₀ value of 0.07 μM for meta- and 0.08 μM for para-carborane at isolated sEH. The ortho-derivative suffered deboronation. The results underline the potential of carboranes as non-natural 3-D pharmacophores to extend the chemical space in drug discovery.

Keywords: 3-D pharmacophore; Amide; Boron; Carborane; Chemical space; Soluble epoxide hydrolase.