Literature DB >> 33738070

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

Naoki Teno1,1, Yusuke Iguchi1, Keisuke Oda1, Yukiko Yamashita1, Arisa Masuda1, Ko Fujimori2, Mizuho Une1,1, Keigo Gohda3.   

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.
© 2021 American Chemical Society.

Entities:  

Year:  2021        PMID： 33738070      PMCID： PMC7957916          DOI： 10.1021/acsmedchemlett.0c00640

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  38 in total

1.  Gut microbiota and intestinal FXR mediate the clinical benefits of metformin.

Authors:  Lulu Sun; Cen Xie; Guang Wang; Yue Wu; Qing Wu; Xuemei Wang; Jia Liu; Yangyang Deng; Jialin Xia; Bo Chen; Songyang Zhang; Chuyu Yun; Guan Lian; Xiujuan Zhang; Heng Zhang; William H Bisson; Jingmin Shi; Xiaoxia Gao; Pupu Ge; Cuihua Liu; Kristopher W Krausz; Robert G Nichols; Jingwei Cai; Bipin Rimal; Andrew D Patterson; Xian Wang; Frank J Gonzalez; Changtao Jiang
Journal:  Nat Med       Date:  2018-11-05       Impact factor: 53.440

2.  Novel type of plasmin inhibitors: providing insight into P4 moiety and alternative scaffold to pyrrolopyrimidine.

Authors:  Naoki Teno; Keigo Gohda; Keiko Wanaka; Yuko Tsuda; Maiko Akagawa; Eriko Akiduki; Mitsuhito Araki; Arisa Masuda; Tadamune Otsubo; Yukiko Yamashita
Journal:  Bioorg Med Chem       Date:  2015-04-10       Impact factor: 3.641

3.  Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists.

Authors:  Carmen Festa; Claudia Finamore; Silvia Marchianò; Francesco Saverio Di Leva; Adriana Carino; Maria Chiara Monti; Federica Del Gaudio; Sara Ceccacci; Vittorio Limongelli; Angela Zampella; Stefano Fiorucci; Simona De Marino
Journal:  ACS Med Chem Lett       Date:  2019-01-10       Impact factor: 4.345

4.  Optically active antifungal azoles. XIII. Synthesis of stereoisomers and metabolites of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456).

Authors:  T Ichikawa; M Yamada; M Yamaguchi; T Kitazaki; Y Matsushita; K Higashikawa; K Itoh
Journal:  Chem Pharm Bull (Tokyo)       Date:  2001-09       Impact factor: 1.645

5.  Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor α (FXRα) in Stabilizing the Homodimerization of the Receptor.

Authors:  Xing Xu; Xin Xu; Peng Liu; Zhi-yuan Zhu; Jing Chen; Hai-an Fu; Li-li Chen; Li-hong Hu; Xu Shen
Journal:  J Biol Chem       Date:  2015-06-22       Impact factor: 5.157

6.  Bile alcohols function as the ligands of membrane-type bile acid-activated G protein-coupled receptor.

Authors:  Yusuke Iguchi; Masafumi Yamaguchi; Hiroyuki Sato; Kenji Kihira; Tomoko Nishimaki-Mogami; Mizuho Une
Journal:  J Lipid Res       Date:  2009-12-18       Impact factor: 5.922

7.  Bile acids: natural ligands for an orphan nuclear receptor.

Authors:  D J Parks; S G Blanchard; R K Bledsoe; G Chandra; T G Consler; S A Kliewer; J B Stimmel; T M Willson; A M Zavacki; D D Moore; J M Lehmann
Journal:  Science       Date:  1999-05-21       Impact factor: 47.728

8.  FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade.

Authors:  Hai Li; Frank Chen; Quan Shang; Luxing Pan; Benjamin L Shneider; John Y L Chiang; Barry M Forman; M Ananthanarayanan; G Stephen Tint; Gerald Salen; Guorong Xu
Journal:  Am J Physiol Gastrointest Liver Physiol       Date:  2005-01       Impact factor: 4.052

9.  Formation of cyclopropanone during cytochrome P450-catalyzed N-dealkylation of a cyclopropylamine.

Authors:  Christopher L Shaffer; Shawn Harriman; Yakov M Koen; Robert P Hanzlik
Journal:  J Am Chem Soc       Date:  2002-07-17       Impact factor: 15.419

10.  Effects of a farnesoid X receptor antagonist on hepatic lipid metabolism in primates.

Authors:  Yuichiro Amano; Mitsuyuki Shimada; Shotaro Miura; Ryutaro Adachi; Ryuichi Tozawa
Journal:  Eur J Pharmacol       Date:  2013-12-19       Impact factor: 4.432
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  3 in total

1.  Discovery of 9,11-Seco-Cholesterol Derivatives as Novel FXR Antagonists.

Authors:  Jia-Xu Zhou; Cui-Na Li; Ya-Meng Liu; Su-Qin Lin; Ying Wang; Cen Xie; Fa-Jun Nan
Journal:  ACS Omega       Date:  2022-05-12

Review 2.  Farnesoid X receptor (FXR): Structures and ligands.

Authors:  Longying Jiang; Huajun Zhang; Desheng Xiao; Hudie Wei; Yongheng Chen
Journal:  Comput Struct Biotechnol J       Date:  2021-04-20       Impact factor: 7.271

3.  Study on the method to avoid infusion-site adverse events following chemotherapeutic treatment with epirubicin and fosaprepitant using immortalized human umbilical vein endothelial cells.

Authors:  Miho Yamasaki; Keisuke Oda; Takashi Ichinose; Marie Mizuguchi; Shoko Tominaga; Kei Omoda; Nobuhiro Mori; Yorinobu Maeda; Toshihiro Nishida; Teruo Murakami
Journal:  Oncol Lett       Date:  2022-09-16       Impact factor: 3.111
  3 in total

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