Discovery and pharmacological profiling of quinoline- and quinoxaline-based phenoxypropanoic acid derivatives as multitarget modulators of PPARα, FXR, and LXRα receptors

Fibrates, derivatives of phenoxypropanoic acid, have long been used in the therapy of dyslipidemia, targeting the nuclear receptor Peroxisome proliferator-activated receptor α (PPARα) in the liver and other organs. To discover novel modulators of metabolism-regulating nuclear receptors, we synthesized and evaluated libraries of novel fibrate derivatives based on 2-(4-(quinolin-2-yloxy)phenoxy)propanoic and 2-(4-(quinoxalin-2-yloxy)phenoxy)propanoic acid. We found that some of the prepared compounds exhibit unique properties activating PPARα and the Farnesoid X receptor (FXR) while simultaneously inhibiting Liver X receptor α (LXR α ) in cellular in vitro assays. Pilot experiments demonstrate that quinoline derivatives 6d and 6e have suitable pharmacokinetic properties and a significant metabolic effect on selected lipid metabolism genes in vivo in mice and human hepatocyte spheroids. Peroral administration of compound 6d to mice fed a high-fat diet decreased the levels of plasma triglycerides and promoted the expression of critical genes of β -oxidation in the liver. We thus propose that we have discovered and pharmacologically profiled new quinoline/quinoxaline phenoxypropanoic acid compounds with combined PPARα/FXR activation and LXRα antagonistic activity, supported by preliminary hepatic target-engagement and in vivo metabolic data. In particular, halogen-substituted 2-(4-(quinolin-2-yloxy)phenoxy)propanoic acid derivatives could be promising multitarget ligands for orchestrating distinct metabolic programs of individual nuclear receptors, supporting their further optimization.