Structure-activity relationship studies of tetrahydroquinolone derivatives as GPR41 modulators

Shinsuke Inuki; Junki Miyamoto; Naoki Hashimoto; Hidenori Shimizu; Hitomi Tabuchi; Atsuko Kawai; Luca C Greiner; Ikuo Kimura; Hiroaki Ohno

doi:10.1016/j.bmcl.2024.129758

Structure-activity relationship studies of tetrahydroquinolone derivatives as GPR41 modulators

Bioorg Med Chem Lett. 2024 Apr 17:107:129758. doi: 10.1016/j.bmcl.2024.129758. Online ahead of print.

Authors

Shinsuke Inuki¹, Junki Miyamoto², Naoki Hashimoto¹, Hidenori Shimizu³, Hitomi Tabuchi¹, Atsuko Kawai¹, Luca C Greiner¹, Ikuo Kimura⁴, Hiroaki Ohno⁵

Affiliations

¹ Department of Bioorganic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
² Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo 183-8509, Japan.
³ Laboratory of Molecular Endocrinology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Noster Inc., Kamiueno, Muko-shi, Kyoto 617-0006, Japan.
⁴ Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo 183-8509, Japan; Laboratory of Molecular Endocrinology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Molecular Endocrinology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan. Electronic address: kimura.ikuo.7x@kyoto-u.ac.jp.
⁵ Department of Bioorganic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan. Electronic address: hohno@pharm.kyoto-u.ac.jp.

PMID: 38641152
DOI: 10.1016/j.bmcl.2024.129758

Abstract

GPR41, a G protein-coupled receptor, serves as a sensor for short-chain fatty acids and plays a crucial role in regulating multiple physiological processes such as the maintenance of metabolic and immune homeostasis. Therefore, the modulation of GPR41 has garnered attention as a potential strategy for the treatment of various disorders. We conducted a structure-activity relationship study on a lead tetrahydroquinolone derivative bearing a 2-(trifluoromethoxy)benzene group that displayed antagonistic activity toward GPR41. Modification of the aryl group attached to the furan moiety revealed that derivatives containing di- or trifluorobenzene, instead of 2-(trifluoromethoxy)benzene, exhibited agonistic activity toward GPR41, comparable with the reported agonistic modulator AR420626. These results suggest that the aryl group plays a pivotal role in regulating the activity of compounds toward GPR41, providing valuable insights for the design of GPR41 modulators.

Keywords: GPR41; Structure–activity relationships; Tetrahydroquinolone.