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
- 주제(기타) Chemistry, Medicinal
- 설명문(일반) [Shim, Soyeon; Krishnaiah, Maddeboina; Sankham, Madhusudana Reddy; Kim, Inha; Shin, Irin; Oh, A. Reum; Lee, Hwa Jeong; Vu, Thi Ngoc Lan; Park, Jongmi; Choi, Sun; Park, Seojeong; Kwon, Youngjoo; Kim, Dae-Kee] Ewha Womans Univ, Coll Pharm, Seoul 03760, South Korea; [Shim, Soyeon; Krishnaiah, Maddeboina; Sankham, Madhusudana Reddy; Kim, Inha; Shin, Irin; Oh, A. Reum; Lee, Hwa Jeong; Vu, Thi Ngoc Lan; Park, Jongmi; Choi, Sun; Park, Seojeong; Kwon, Youngjoo; Kim, Dae-Kee] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Shim, Soyeon; Kim, Dae-Kee] EWHA DrugDesignHouse, Seoul 03760, South Korea; [Krishnaiah, Maddeboina] Atrium Hlth LevineCancer Inst, MTT Lab, Dept Translat Res, 1021 Morehead Med Dr, Charlotte, NC 28204 USA; [Sankham, Madhusudana Reddy] H 85-1 Saraswathi Nagar, Secunderabad 500015, India; [Lee, Yoseob; Fang, Sungsoon] Yonsei Univ, Grad Sch Med Sci, Dept Biochem & Mol Biol, Coll Med,Brain Project Korea 21, Seoul 03722, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 AMER CHEMICAL SOC
- 발행년도 2022
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000194488
- 본문언어 영어
- Published As https://doi.org/10.1021/acs.jmedchem.2c00641
- PubMed https://pubmed.ncbi.nlm.nih.gov/35797110
초록/요약
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.
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