Discovery of FXR/PPARγ dual partial agonist

Yukiko Yamashita; Keigo Gohda; Yusuke Iguchi; Ko Fujimori; Keisuke Oda; Arisa Masuda; Mizuho Une; Naoki Teno

doi:10.1016/j.bmc.2023.117238

Discovery of FXR/PPARγ dual partial agonist

Bioorg Med Chem. 2023 May 1:85:117238. doi: 10.1016/j.bmc.2023.117238. Epub 2023 Mar 24.

Authors

Yukiko Yamashita¹, Keigo Gohda², Yusuke Iguchi¹, Ko Fujimori³, Keisuke Oda¹, Arisa Masuda⁴, Mizuho Une⁵, Naoki Teno⁶

Affiliations

¹ Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.
² Computer-Aided Molecular Modeling Research Center, Kansai (CAMM-Kansai), Nishinomiya 663-8241, Japan.
³ Department of Pathobiochemistry, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569-1094, Japan.
⁴ Graduate School of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.
⁵ Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan; Graduate School of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.
⁶ Graduate School of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan; Faculty of Clinical Nutrition, Hiroshima International University, Kure, Hiroshima 737-0112, Japan. Electronic address: n-teno@hirokoku-u.ac.jp.

PMID: 37028120
DOI: 10.1016/j.bmc.2023.117238

Abstract

Farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)γ are nuclear receptor 1 superfamily of transcription factors. FXR and PPARγ agonists have been individually investigated in clinical trial of anti-diabetic agents in the patients with nonalcoholic fatty liver disease (NAFLD). Regarding recent agonist development, the partial agonists for FXR and PPARγ are drawing attention from the standpoint of avoiding overactive responses caused by full agonists. In this article, we report that 18 with a benzimidazole scaffold possesses FXR/PPARγ dual partial agonistic activity. In addition, 18 shares the ability to reduce cyclin-dependent kinase 5-mediated phosphorylation of PPARγ-Ser273 and the metabolic stability in mouse liver microsome assay. To date, there are no published reports on FXR/PPARγ dual partial agonists with biological profiles similar to 18. Thus, the analog would be a feasible candidate as an unprecedented approach to NAFLD associated with type 2 diabetes mellitus.

Keywords: Benzimidazole; Dual partial agonist; FXR; NAFLD; PPARγ; Phosphorylation of PPARγ-Ser273; T2DM.

MeSH terms

Animals
Diabetes Mellitus, Type 2* / drug therapy
Hypoglycemic Agents / pharmacology
Mice
Non-alcoholic Fatty Liver Disease* / drug therapy
PPAR gamma / agonists
Transcription Factors

Substances

PPAR gamma
Transcription Factors
Hypoglycemic Agents