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Development of Selective TGR5 Ligands Based on the 5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalene Skeleton |
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| Authors: | Ryusei Terui Yuta Yanase Dr Hidetomo Yokoo Prof Yoshitomo Suhara Prof Makoto Makishima Dr Yosuke Demizu Dr Takashi Misawa |
| Affiliation: | 1. National Institute of Health Sciences, 1 3–25-26, Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-9501 Japan
Faculty of Bioscience and Engineering, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama-shi, Saitama, 337-8570 Japan;2. National Institute of Health Sciences, 1 3–25-26, Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-9501 Japan Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Yokohama, Kanagawa, 230-0045 Japan;3. National Institute of Health Sciences, 1 3–25-26, Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-9501 Japan;4. Faculty of Bioscience and Engineering, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama-shi, Saitama, 337-8570 Japan;5. Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610 Japan |
| 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. |
| Keywords: | GPCR TGR5 Bile acids Retinoid FXR |
