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

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.