TY - JOUR
T1 - Development of Selective TGR5 Ligands Based on the 5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalene Skeleton
AU - Terui, Ryusei
AU - Yanase, Yuta
AU - Yokoo, Hidetomo
AU - Suhara, Yoshitomo
AU - Makishima, Makoto
AU - Demizu, Yosuke
AU - Misawa, Takashi
N1 - Funding Information:
We thank Prof Hiroyuki Kagechika (Tokyo medical and dental university) for valuable advice. This work was supported in part by grants from the Japan Society for the Promotion of Science (KAKENHI, Grants 18K14880 to T.M., 18H05502 to Y.D.), the Terumo Foundation for Life Sciences and Arts (to T.M. and Y.D.), the Takeda Science Foundation (to T.M., and Y.D.), the Naito Foundation (to Y.D.), the NOVARTIS Foundation (Japan) for the Promotion of Science (to Y.D.), and Grant for Basic Science Research Project from the Sumitomo Foundation (to Y.D.). We would like to thank Editage (www.editage.com) for English language editing.
Funding Information:
We thank Prof Hiroyuki Kagechika (Tokyo medical and dental university) for valuable advice. This work was supported in part by grants from the Japan Society for the Promotion of Science (KAKENHI, Grants 18K14880 to T.M., 18H05502 to Y.D.), the Terumo Foundation for Life Sciences and Arts (to T.M. and Y.D.), the Takeda Science Foundation (to T.M., and Y.D.), the Naito Foundation (to Y.D.), the NOVARTIS Foundation (Japan) for the Promotion of Science (to Y.D.), and Grant for Basic Science Research Project from the Sumitomo Foundation (to Y.D.). We would like to thank Editage (www.editage.com) for English language editing.
Publisher Copyright:
© 2020 Wiley-VCH GmbH
PY - 2021/2/4
Y1 - 2021/2/4
N2 - 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.
AB - 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.
KW - Bile acids
KW - FXR
KW - GPCR
KW - Retinoid
KW - TGR5
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U2 - 10.1002/cmdc.202000567
DO - 10.1002/cmdc.202000567
M3 - Article
C2 - 32969181
AN - SCOPUS:85092890182
SN - 1860-7179
VL - 16
SP - 458
EP - 462
JO - Farmaco
JF - Farmaco
IS - 3
ER -