Discovery of Orally Active and Nonsteroidal Farnesoid X Receptor (FXR) Antagonist with Propensity for Accumulation and Responsiveness in Ileum

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

doi:10.1021/acsmedchemlett.0c00640

Discovery of Orally Active and Nonsteroidal Farnesoid X Receptor (FXR) Antagonist with Propensity for Accumulation and Responsiveness in Ileum

ACS Med Chem Lett. 2021 Feb 24;12(3):420-425. doi: 10.1021/acsmedchemlett.0c00640. eCollection 2021 Mar 11.

Authors

Naoki Teno^{1

1}, Yusuke Iguchi¹, Keisuke Oda¹, Yukiko Yamashita¹, Arisa Masuda¹, Ko Fujimori², Mizuho Une^{1

1}, Keigo Gohda³

Affiliations

¹ Graduate School of Pharmaceutical Sciences, Faculty of Clinical Nutrition, and Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
² Department of Pathobiochemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
³ Computer-Aided Molecular Modeling Research Center, Kansai (CAMM-Kansai), 3-32-302, Tsuto-Otsuka, Nishinomiya 663-8241, Japan.

Abstract

We describe the discovery of analog 15 (FLG249), which is an orally active and nonsteroidal farnesoid X receptor (FXR) antagonist in mice with unique profiles, such as a propensity for ileum distribution and the significant control in the expression level of three FXR target genes in mouse ileum. Key design features incorporated in 15 were the introduction of metabolically stable groups in potent and metabolically labile antagonist 9. Our pursuit ultimately identified FXR antagonist 15, which has enabled its assessment in a drug discovery program.