Discovery of (E)-3-(3-((2-Cyano-4′-dimethylaminobiphenyl-4-ylmethyl)cyclohexanecarbonylamino)-5-fluorophenyl)acrylic Acid Methyl Ester, an Intestine-Specific, FXR Partial Agonist for the Treatment of Nonalcoholic Steatohepatitis

Soyeon Shim, Maddeboina Krishnaiah, Madhusudana Reddy Sankham, Inha Kim, Yoseob Lee, Irin Shin, A. Reum Oh, Hwa Jeong Lee, Thi Ngoc Lan Vu, Jongmi Park, Sun Choi, Seojeong Park, Youngjoo Kwon, Sungsoon Fang, Dae Kee Kim

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


A series of fexaramine analogs were synthesized and evaluated to develop an intestine-selective/specific FXR partial agonist. Introduction of both a CN substituent at the C-2 in the biphenyl ring and a fluorine at the C-5 in the aniline ring in fexaramine markedly increased FXR agonistic activity. 27c showed 53 ± 3% maximum efficacy relative to GW4064 in an FXR agonist assay. A substantial amount of 27c was absorbed in the intestine after oral administration in rats, and then it was rapidly metabolized to inactive carboxylic acid 44 by serum esterases. In CDAHFD-fed mice, oral administration of 27c strongly induced multiple intestinal FXR target genes, FGF15, SHP, IBABP, and OST-α, but failed to activate SHP in the liver. 27c significantly reduced the liver fibrogenesis area, hepatic fibrosis markers, and serum level of AST. Rational optimization of fexaramine has led to the identification of an intestine-specific FXR partial agonist 27c.

Original languageEnglish
Pages (from-to)9974-10000
Number of pages27
JournalJournal of Medicinal Chemistry
Issue number14
StatePublished - 28 Jul 2022

Bibliographical note

Funding Information:
This work was supported in part by the Mid-career Researcher Program (NRF-2020R1A2C2101636), Medical Research Center (MRC) grant (NRF-2018R1A5A2025286), Ministry of Health and Welfare (HR18C0012) grant (to S.F.), Bio & Medical Technology Development Program (NRF-2019M3E5D4065251) funded by the Ministry of Science and ICT and the Ministry of Health and Welfare through the National Research Foundation of Korea, and Ewha Womans University Research grant of 2021 (to S.C.).

Publisher Copyright:
© 2022 American Chemical Society.


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