N1-Substituted benzimidazole scaffold for farnesoid X receptor (FXR) agonists accompanying prominent selectivity against vitamin D receptor (VDR). Issue 14 (15th July 2020)

• Record Type: Journal Article
• Authors: Masuda, Arisa; Gohda, Keigo; Iguchi, Yusuke; Fujimori, Ko; Yamashita, Yukiko; Oda, Keisuke; Une, Mizuho; Teno, Naoki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 14(2020)
• Publication Date: 2020-07-15
• Subjects: FXR Farnesoid X receptor -- CDCA Chenodeoxycholic acid -- CYP7A1 Cholesterol 7α-hydroxylase -- BSEP Bile salt export pump -- SHP Small heterodimer partner -- OSTα Organic solute transporter α -- CAR Constitute androstane receptor -- PXR Pregnane X receptor -- RXRα Retinoid X receptor α -- 9-cis-RA 9-cis-Retinoic acid -- 1 25-OH-VD3, 1α, 25-Dihydroxy-vitamin D3 -- TGR5 Transmembrane G protein-coupled receptor 5 -- FGF15 Fibroblast growth factor 15 -- NASH Non-alcoholic steatohepatitis -- LBD Ligand binding domain -- TR-FRET Time-resolved fluorescence resonance energy transfer -- RT-PCR Reverse transcription polymerase chain reaction -- BMP-2 Bone morphogenetic protein-2 -- ST-2 MSCs Mouse bone marrow-derived mesenchymal stem cell (MSC)-like ST2 cells -- GS Guggulsterone -- ALP Alkaline phosphatase -- SAR Structure-activity relationship -- Et3N Triethylamine -- DMF N, N-Dimethylformamide -- THF Tetrahydrofuran -- Boc tert-Butoxycarbonyl -- HOAt 1-Hydroxy-7-azabenzotriazole -- WSCI.HCl 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride -- TBAF tetra-n-Butylammonium fluoride; FXR agonist -- Benzimidazole -- Osteoblast differentiation; 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.2020.115512
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. With respect to the bone metabolism, FXR positively regulates bone metabolism through both bone formation and resorption of the bone remodeling pathways. Some of FXR agonists possessing isoxazole moiety are undergoing clinical trials for the treatment of non-alcoholic steatohepatitis. To date, therefore, the activation of FXR leads to considerable interest in FXR as potential therapeutic targets. We have identified a series of nonsteroidal FXR agonists bearing N 1 -methyl benzimidazole and isoxazole moieties that are bridged with aromatic derivatives. They showed affinity to FXR, but also weak affinity toward the vitamin D receptor (VDR) that involves regulation of calcium and phosphate homeostasis and is activated by bile acids. The deployment of FXR agonists without activity against VDR as off-target is therefore crucial in the development of FXR ligands. Our efforts focusing on increasing the agonist properties towards FXR led to the discovery of 19, which activates FXR at and below nanomolar levels (EC50 = 26.5 ± 10.5 nM TR-FRET and 0.8 ± 0.2 nM luciferase, respectively) and functions as a FXR agonist: the affinity toward FXR over eight nuclear receptors, including VDR [IC50 (VDR) / EC50 (FXR) > 5000] and TGR5, effects FXR target genes, and activates bone morphogenetic protein-2-induced differentiation of mouse bone marrow-derived mesenchymal stem cell-like ST2 cells into osteoblast.