Design and Structural Optimization of Dual FXR/PPARδ Activators

Abstract

Nonalcoholic steatohepatitis (NASH) is considered as severe hepatic manifestation of the metabolic syndrome and has alarming global prevalence. The ligand-activated transcription factors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) δ have been validated as molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPARδ-mediated activity and hepatic effects of FXR activation appear as a promising multitarget approach. We have designed a minimal dual FXR/PPARδ activator scaffold by rational fusion of pharmacophores derived from selective agonists. Our dual agonist lead compound exhibited weak agonism on FXR and PPARδ and was structurally refined to a potent and balanced FXR/PPARδ activator in a computer-aided fashion. The resulting dual FXR/PPARδ modulator comprises high selectivity over related nuclear receptors and activates the two target transcription factors in native cellular settings.

Development and in vitro Profiling of Dual FXR/LTA4H Modulators

“…Following this strategy, we have previously developed dual modulators to target, for example, farnesoid X receptor (FXR) and soluble epoxide hydrolase (sEH),[ 6 , 7 , 8 ] or FXR and peroxisome proliferator‐activated receptors (PPARs). [ 9 , 10 ] Strong therapeutic efficacy of such multi‐target agents in preclinical NASH models[ 10 , 11 ] corroborates the potential of designed polypharmacology in this indication. We further hypothesize that a combination of partial FXR activation [12] and inhibition of leukotriene A4 hydrolase (LTA4H) can efficiently counteract NAFLD/NASH.…”

“…One such disease is NASH which arises from metabolic imbalance, inflammation and fibrotic transformation in liver, and hence demands therapeutic intervention against several factors. Previous studies have shown that designed multiple ligands of FXR and sEH,[ 6 , 7 , 8 ] PPARα and PPARδ [35] as well as FXR and PPARδ[ 9 , 10 ] hold potential to achieve superior efficacy in experimental NASH treatment. Here we report a novel designed multiple ligand that concomitantly activates FXR and inhibits LTA4H.…”

“…Designed polypharmacology addressing complementary pathomechanisms may, therefore, offer access to synergistic efficacy in this complex disease. Following this strategy, we have previously developed dual modulators to target, for example, farnesoid X receptor (FXR) and soluble epoxide hydrolase (sEH), [6–8] or FXR and peroxisome proliferator‐activated receptors (PPARs) [9,10] . Strong therapeutic efficacy of such multi‐target agents in preclinical NASH models [10,11] corroborates the potential of designed polypharmacology in this indication.…”

Multi-Target Drugs for Kidney Diseases

“…23,24 These include combining FXR agonism with PPAR agonism. 64,65 FXR agonism has been combined with PPAR and combined PPAR/ agonism. 64,65 These combined FXR and PPAR agonists have demonstrated promise in liver diseases but have yet to be tested in kidney diseases.…”

“…64,65 These combined FXR and PPAR agonists have demonstrated promise in liver diseases but have yet to be tested in kidney diseases. 64,65 PPAR agonism has also been coupled to glucokinase activation and AT1 receptor inhibition. 23,24 Renin angiotensin system angiotensin converting enzyme (ACE) inhibition has been combined with dipeptidyl-peptidase 4 (DPP4) inhibition.…”