Second-Generation Dual FXR/sEH Modulators with Optimized Pharmacokinetics

Non-alcoholic steatohepatitis
(NASH) presents as an epidemic chronic
liver disease that is closely associated with metabolic disorders
and involves hepatic steatosis, inflammation, and fibrosis as key
factors. Despite the enormous global prevalence of NASH, effective
pharmacological interventions are lacking. Based on the hypothesis
that the multifactorial condition NASH may benefit from combined multiple
modes of action for enhanced therapeutic efficacy, we have previously
developed dual FXR activators/sEH inhibitors (FXRa/sEHi) and observed
remarkable antifibrotic effects upon their use in rodent NASH models.
However, these first-generation FXRa/sEHi were characterized by moderate
metabolic stability and short in vivo half-life. Aiming to overcome
these pharmacokinetic drawbacks, we have systematically studied the
structure–activity and structure–stability relationships
of the chemotype and obtained second-generation FXRa/sEHi with improved
pharmacokinetic parameters. With high plasma exposure, a half-life
greater than 5 h, and similar dual potency on the intended targets, 13 presents as a substantially optimized FXRa/sEHi for late-stage
preclinical development.