Discovery of FXR/PPARγ dual partial agonist. (1st May 2023)

• Record Type: Journal Article
• Authors: Yamashita, Yukiko; Gohda, Keigo; Iguchi, Yusuke; Fujimori, Ko; Oda, Keisuke; Masuda, Arisa; Une, Mizuho; Teno, Naoki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 85(2023)
• Publication Date: 2023-05-01
• Subjects: FXR -- PPARγ -- Dual partial agonist -- Benzimidazole -- Phosphorylation of PPARγ-Ser273 -- NAFLD -- T2DM; FXR farnesoid X receptor -- PPAR peroxisome proliferator-activated receptor -- NR nuclear receptor -- CDCA chenodeoxycholic acid -- GS guggulsterone -- CYP7A1 cholesterol 7α-hydroxylase -- SHP small heterodimer partner -- CAR constitutive androstane receptor -- PXR pregnane X receptor -- RXRα retinoid X receptor α -- 9-cis-RA 9-cis-retinoic acid -- SREBP sterol regulatory element binding protein -- FGF fibroblast growth factor -- OST organic solute transporter -- FAS fatty acid synthase -- BSEP bile salt export pump -- TGR5 transmembrane G protein-coupled receptor 5 -- CDK cyclin-dependent kinase -- OCT obeticholic acid -- LBD ligand binding domain -- GLUT4 glucose transporter 4 -- SCD stearoyl-CoA desaturase -- TR-FRET time-resolved fluorescence resonance energy transfer -- TDZ thiazolidinedione -- MLM mouse liver microsomes -- NASH nonalcoholic steatohepatitis -- NAFLD nonalcoholic fatty liver disease -- T2DM type 2 diabetes mellitus -- Et3N triethylamine -- DMF N, N-dimethylformamide -- THF tetrahydrofuran -- Boc tert-butoxycarbonyl -- HOAt 1-hydroxy-7-azabenzotriazole -- WSCI.HCl 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride -- HR-MS high resolution mass spectrometer -- RP-HPLC reversed phase high performance liquid chromatography; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2023.117238
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)γ are nuclear receptor 1 superfamily of transcription factors. FXR and PPARγ agonists have been individually investigated in clinical trial of anti-diabetic agents in the patients with nonalcoholic fatty liver disease (NAFLD). Regarding recent agonist development, the partial agonists for FXR and PPARγ are drawing attention from the standpoint of avoiding overactive responses caused by full agonists. In this article, we report that 18 with a benzimidazole scaffold possesses FXR/PPARγ dual partial agonistic activity. In addition, 18 shares the ability to reduce cyclin-dependent kinase 5-mediated phosphorylation of PPARγ-Ser273 and the metabolic stability in mouse liver microsome assay. To date, there are no published reports on FXR/PPARγ dual partial agonists with biological profiles similar to 18. Thus, the analog would be a feasible candidate as an unprecedented approach to NAFLD associated with type 2 diabetes mellitus.