A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase to Counter Nonalcoholic Steatohepatitis
Dr. Daniel Merk, ETH Zürich
Published in: Journal of Medicinal Chemistry 2017, 60(18), 7703-7724
The non-alcoholic fatty liver and the non-alcoholic steatohepatitis as their advanced form are regarded as hepatic manifestations of the metabolic syndrome. The research group led by Dr. Merk has developed an experimental drug that simultaneously modulates two biological target structures whose respective efficacy in non-alcoholic steatohepatitis has been proven in clinical studies and functional animal models. In particular, the activation of the farnesoid X-receptor (FXR), which showed antisteatoid and antifibrotic effects in clinical studies, combined with the inhibition of soluble epoxide hydrolase (sEH) as an anti-inflammatory strategy, promises synergies. To exploit this dual concept, the team has developed agents that exert partial FXR agonism and sEH-inhibiting activity. The combination of known pharmacophores and the systematic investigation of the structure-activity relationship at both targets resulted in dual modulators with low nanomolar potency. Extensive in vitro characterization confirmed high dual efficacy in the cellular context combined with low toxicity, and the pilot in vivo data showed positive pharmacokinetics and involvement in both targets in vivo.