3 years ago

A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase To Counter Nonalcoholic Steatohepatitis

A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase To Counter Nonalcoholic Steatohepatitis
Alexander Paulke, Gerd Geisslinger, Jurema Schmidt, Tim Weiser, Ewgenij Proschak, Tamara Goebel, Dieter Steinhilber, Jan Heering, Sandra Wittmann, Astrid Kahnt, Marco Rotter, Carlo Angioni, Lilia Weizel, Daniel Merk, Mario Wurglics, Astrid Kaiser
Nonalcoholic steatohepatitis arising from Western diet and lifestyle is characterized by accumulation of fat in liver causing inflammation and fibrosis. It evolves as serious health burden with alarming incidence, but there is no satisfying pharmacological therapy to date. Considering the disease’s multifactorial nature, modulation of multiple targets might provide superior therapeutic efficacy. In particular, farnesoid X receptor (FXR) activation that revealed antisteatotic and antifibrotic effects in clinical trials combined with inhibition of soluble epoxide hydrolase (sEH) as anti-inflammatory strategy promises synergies. To exploit this dual concept, we developed agents exerting partial FXR agonism and sEH inhibitory activity. Merging known pharmacophores and systematic exploration of the structure–activity relationship on both targets produced dual modulators with low nanomolar potency. Extensive in vitro characterization confirmed high dual efficacy in cellular context combined with low toxicity, and pilot in vivo data revealed favorable pharmacokinetics as well as engagement on both targets in vivo.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00398

DOI: 10.1021/acs.jmedchem.7b00398

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