Development of Selective TGR5 Ligands Based on the 5, 6, 7, 8‐Tetrahydro‐5, 5, 8, 8‐tetramethylnaphthalene Skeleton. (21st October 2020)

• Record Type: Journal Article
• Authors: Terui, Ryusei; Yanase, Yuta; Yokoo, Hidetomo; Suhara, Yoshitomo; Makishima, Makoto; Demizu, Yosuke; Misawa, Takashi
• Is Part Of: ChemMedChem. Volume 16:Number 3(2021)
• Page Start: 458
• Page End: 462
• Publication Date: 2020-10-21
• Subjects: GPCR -- TGR5 -- Bile acids -- Retinoid -- FXR; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000567
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: TGR5, a G‐protein‐coupled receptor (GPCR), plays an important role in several physiological functions. TGR5 activation through bile acids induces an increase in energy expenditure. Therefore, synthetic TGR5 ligands could be useful for the treatment of obesity or dyslipidemia. In this study, we designed and synthesized a set of TGR5 ligands with a 5, 6, 7, 8‐tetrahydro‐5, 5, 8, 8‐tetramethylnaphthalene (TMN) skeleton, and evaluated their TGR5 agonistic activity. We also investigated the selectivity of the synthesized compounds for TGR5 relative to the farnesoid X receptor (FXR) and retinoic acid receptor (RAR). Our results show that compound 4 b [ N ‐(2‐chlorophenyl)‐5, 6, 7, 8‐tetrahydro‐5, 5, 8, 8‐tetramethyl‐2‐naphthalenecarboxamide] exhibited potent TGR5 agonist activity with an IC50 value of 8.4 nM without significant cytotoxicity. In addition, compound 4 b showed only slight agonistic activity toward FXR and RAR at 1 μM treatment. These data indicate that compound 4 b is a selective TGR5 agonist, and could be a promising therapeutic agent for dyslipidemia. Abstract : Bile acid receptor agonism : TGR5 ligands based on the tetramethylnaphthalene (TMN) skeleton were designed and synthesized. They were assayed for their TGR5 agonism and GLP‐1 secretion activity. Compound 4 b exhibited potent TGR5 agonistic activity and decreased secreted GLP‐1. Moreover, compound 4 b did not exhibit agonistic activity against other nuclear receptors such as FXR and RARs. Homology modeling and docking studies revealed the essential amino acid residues of TGR5 for binding compound 4 b .