Current Clinical Trial Status and Future Prospects of PPAR-Targeted Drugs for Treating Nonalcoholic Fatty Liver Disease

Abstract

The number of patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is increasing globally and is raising serious concerns regarding the increasing medical and economic burden incurred for their treatment. The progression of NASH to more severe conditions such as cirrhosis and hepatocellular carcinoma requires liver transplantation to avoid death. Therefore, therapeutic intervention is required in the NASH stage, although no therapeutic drugs are currently available for this. Several anti-NASH candidate drugs have been developed that enable treatment via the modulation of distinct signaling cascades and include a series of drugs targeting peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) that are considered to be attractive because they can regulate both systemic lipid metabolism and inflammation. Multiple PPAR dual/pan agonists have been developed but only a few of them have been evaluated in clinical trials for NAFLD/NASH. Herein, we review the current clinical trial status and future prospects of PPAR-targeted drugs for treating NAFLD/NASH. In addition, we summarize our recent findings on the binding modes and the potencies/efficacies of several candidate PPAR dual/pan agonists to estimate their therapeutic potentials against NASH. Considering that the development of numerous PPAR dual/pan agonists has been abandoned because of their serious side effects, we also propose a repositioning of the already approved, safety-proven PPAR-targeted drugs against NAFLD/NASH.

Keywords: NAFLD; NASH; PPAR; X-ray crystallography; bezafibrate; dual/pan agonist; lanifibranor; pemafibrate; saroglitazar.

Figure 1

Binding modes in the PPAR cocrystal structures and the potencies/efficacies in transactivation and PGC1α recruitment activity of lanifibranor (A), elafibranor (B), saroglitazar (C), and seladelpar (D) against PPARα/δ/γ. (a) Merged magnified views of ligands bound to the PPARα (magenta)/δ (green)/γ (light blue)-ligand binding domains revealed by X-ray diffraction analyses of cocrystals; Protein Data Bank (PDB) IDs are shown. PPARδ/γ–elafibranor and PPARδ–saroglitazar cocrystals were not obtained. (b–e) Potencies as EC₅₀ values (µM) (b,d), and efficacies as % of the maximal responses triggered by the PPARα/δ/γ-selective full agonists (GW7647, GW501516, and GW1929, respectively) (c,e) in GAL4-based transactivation assay in Cos-7 cells (b,c) and time-resolved fluorescence energy transfer (TR-FRET)-based PGC1α coactivator recruitment assay (d,e). In each ternary plot, the degrees of potency and efficacy are shown by the axes from the triangle center to the three vertices (PPARα in magenta, PPARδ in green, and PPARγ in light blue) on logarithmic (b,d) and linear scales (c,e), respectively. All structural and functional data were published by our group [11,12,13,14,20].

Figure 1

Binding modes in the PPAR cocrystal structures and the potencies/efficacies in transactivation and PGC1α recruitment activity of lanifibranor (A), elafibranor (B), saroglitazar (C), and seladelpar (D) against PPARα/δ/γ. (a) Merged magnified views of ligands bound to the PPARα (magenta)/δ (green)/γ (light blue)-ligand binding domains revealed by X-ray diffraction analyses of cocrystals; Protein Data Bank (PDB) IDs are shown. PPARδ/γ–elafibranor and PPARδ–saroglitazar cocrystals were not obtained. (b–e) Potencies as EC₅₀ values (µM) (b,d), and efficacies as % of the maximal responses triggered by the PPARα/δ/γ-selective full agonists (GW7647, GW501516, and GW1929, respectively) (c,e) in GAL4-based transactivation assay in Cos-7 cells (b,c) and time-resolved fluorescence energy transfer (TR-FRET)-based PGC1α coactivator recruitment assay (d,e). In each ternary plot, the degrees of potency and efficacy are shown by the axes from the triangle center to the three vertices (PPARα in magenta, PPARδ in green, and PPARγ in light blue) on logarithmic (b,d) and linear scales (c,e), respectively. All structural and functional data were published by our group [11,12,13,14,20].

Figure 2

Binding modes in the PPAR cocrystal structures and the potencies/efficacies in transactivation and PGC1α recruitment activity of fenofibric acid (the active metabolite of fenofibrate) (A), pemafibrate (B), pioglitazone (C), and bezafibrate (D) against PPARα/δ/γ. (a) Merged magnified views of ligands bound to the PPARα (magenta)/δ (green)/γ (light blue)-ligand binding domain revealed by X-ray diffraction analyses of cocrystals; PDB IDs are shown. PPARδ–fenofibric acid and PPARα/δ–pioglitazone cocrystals were not obtained. (b–e) Potencies as EC₅₀ values (µM) (b,d) and efficacies as % of the maximal responses triggered by the PPARα/δ/γ–selective full agonists (GW7647, GW501516, and GW1929, respectively) (c,e) in GAL4-based transactivation assay in Cos-7 cells (b,c) and TR-FRET-based PGC1α coactivator recruitment assays (d,e). In each ternary plot, the degrees of potency and efficacy are shown by the axes from the triangle center to the three vertices (PPARα in magenta, PPARδ in green, and PPARγ in light blue) on logarithmic (b,d) and linear scales (c,e), respectively. All structural (except for Figure 2C(a)) and functional data were published by our group [11,12,13,14,20].