1-Benzyl-4-phenyl-1H-1, 2, 3-triazoles improve the transcriptional functions of estrogen-related receptor γ and promote the browning of white adipose. Issue 13 (1st July 2015)

• Record Type: Journal Article
• Authors: Xu, Shilin; Mao, Liufeng; Ding, Ping; Zhuang, Xiaoxi; Zhou, Yang; Yu, Lei; Liu, Yingxue; Nie, Tao; Xu, Tingting; Xu, Yong; Liu, Jinsong; Smaill, Jeff; Ren, Xiaomei; Wu, Donghai; Ding, Ke
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 13(2015)
• Page Start: 3751
• Page End: 3760
• Publication Date: 2015-07-01
• Subjects: ERR estrogen-related receptor -- WAT white adipose tissue -- BAT brown adipose tissue -- PET positron-emission-tomography -- FGF21 fibroblast growth factor 21 -- MOA mechanisms of action -- UCP1 uncoupling protein 1 -- SHP small heterodimer partner -- ATP5b ATP synthase 5b -- MCAD medium-chain acyl-coenzyme A dehydrogenase -- MEF mouse embryonic fibroblasts -- Prdm16 PR domain containing 16 -- PGC-1α peroxisome proliferator-activated receptor-γ coactivator 1α -- CS citrate synthase -- CPT1 carnitine palmitoyltransferase-1 -- COXII cytochrome c oxidase subunit II -- SDH succinate dehydrogenase -- ITC isothermal titration calorimetry -- CD circular dichroism -- LBD ligand binding domain -- Tm melting temperature; Estrogen-related receptor γ -- Adipose browning -- Drug design -- Triazole; 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.2015.03.082
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The estrogen-related receptor γ (ERRγ) is a potential molecular target for the development of small molecules to stimulate the adipose browning process, which may represent a novel attractive strategy to treat obesity related disorders. The receptor possesses a very small ligand binding cavity and therefore identification of small molecule ERRγ modulators is a considerable challenge. We have successfully designed and synthesized a series of 1-benzyl-4-phenyl-1 H -1, 2, 3-triazoles and demonstrated that they improve the transcriptional functions of ERRγ, potently elevating both the mRNA levels and the protein levels of ERRγ downstream targets. One of the most promising compounds, 4-(1-(4-iso-propylbenzyl)-1 H -1, 2, 3-triazol-4-yl)benzene-1, 2-diol (2e ) was further shown to directly bind with the ERRγ ligand binding domain (ERRγ-LBD) in an isothermal calorimetric (ITC) assay and to thermally stabilize ERRγ-LBD protein by increasing its melting temperature ( T m ) as demonstrated by circular dichroism (CD) spectroscopy. Furthermore, 2e potently stimulates the adipocyte browning process and induces mitochondrial biogenesis both in vitro and in vivo, suggesting the considerable therapeutic potential of this compound for the treatment of obesity and related disorders.