Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists

Abstract Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile aci...

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Autores principales:	Sachiho Miyata, Yuji Kawashima, Miku Sakai, Masaya Matsubayashi, Keisuke Motoki, Yui Miyajima, Yousuke Watanabe, Noriko Chikamatsu, Tetsuya Taniguchi, Ryukou Tokuyama
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2f20bd812afb4befbc78eaa3e510a946
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spelling	oai:doaj.org-article:2f20bd812afb4befbc78eaa3e510a9462021-12-02T16:56:02ZDiscovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists10.1038/s41598-021-88493-02045-2322https://doaj.org/article/2f20bd812afb4befbc78eaa3e510a9462021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88493-0https://doaj.org/toc/2045-2322Abstract Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight for one week. Compound 20p dose-dependently induced small heterodimer partner (SHP) mRNA and decreased cytochrome P450 7A1 (CYP7A1) in the liver at 10 and 30 mg/kg, respectively, which were used as FXR agonist markers. Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.Sachiho MiyataYuji KawashimaMiku SakaiMasaya MatsubayashiKeisuke MotokiYui MiyajimaYousuke WatanabeNoriko ChikamatsuTetsuya TaniguchiRyukou TokuyamaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sachiho Miyata Yuji Kawashima Miku Sakai Masaya Matsubayashi Keisuke Motoki Yui Miyajima Yousuke Watanabe Noriko Chikamatsu Tetsuya Taniguchi Ryukou Tokuyama Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists
description	Abstract Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight for one week. Compound 20p dose-dependently induced small heterodimer partner (SHP) mRNA and decreased cytochrome P450 7A1 (CYP7A1) in the liver at 10 and 30 mg/kg, respectively, which were used as FXR agonist markers. Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.
format	article
author	Sachiho Miyata Yuji Kawashima Miku Sakai Masaya Matsubayashi Keisuke Motoki Yui Miyajima Yousuke Watanabe Noriko Chikamatsu Tetsuya Taniguchi Ryukou Tokuyama
author_facet	Sachiho Miyata Yuji Kawashima Miku Sakai Masaya Matsubayashi Keisuke Motoki Yui Miyajima Yousuke Watanabe Noriko Chikamatsu Tetsuya Taniguchi Ryukou Tokuyama
author_sort	Sachiho Miyata
title	Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists
title_short	Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists
title_full	Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists
title_fullStr	Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists
title_full_unstemmed	Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists
title_sort	discovery, optimization, and evaluation of non-bile acid fxr/tgr5 dual agonists
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2f20bd812afb4befbc78eaa3e510a946
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Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists

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