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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
- Title
- 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
- Authors
- Shim, Soyeon; Krishnaiah, Maddeboina; Sankham, Madhusudana Reddy; Kim, Inha; Lee, Yoseob; Shin, Irin; Oh, A. Reum; Lee, Hwa Jeong; Vu, Thi Ngoc Lan; Park, Jongmi; Choi, Sun; Park, Seojeong; Kwon, Youngjoo; Fang, Sungsoon; Kim, Dae-Kee
- Ewha Authors
- 이화정; 김대기; 권영주; 최선; 박서정
- SCOPUS Author ID
- 이화정; 김대기; 권영주; 최선; 박서정
- Issue Date
- 2022
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- ISSN
- 0022-2623
1520-4804
- Citation
- JOURNAL OF MEDICINAL CHEMISTRY vol. 65, no. 14, pp. 9974 - 10000
- Publisher
- AMER CHEMICAL SOC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- 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-alpha, 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.
- DOI
- 10.1021/acs.jmedchem.2c00641
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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