Literature DB >> 30996787

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

Carmen Festa1, Claudia Finamore1, Silvia Marchianò2, Francesco Saverio Di Leva1, Adriana Carino2, Maria Chiara Monti3, Federica Del Gaudio3, Sara Ceccacci3, Vittorio Limongelli1,4, Angela Zampella1, Stefano Fiorucci2, Simona De Marino1.   

Abstract

Recent findings have shown that Farnesoid X Receptor (FXR) antagonists might be useful in the treatment of cholestasis and related metabolic disorders. In this paper, we report the discovery of a new chemotype of FXR antagonists featured by a 3,5-disubstituted oxadiazole core. In total, 35 new derivatives were designed and synthesized, and notably, compounds 3f and 13, containing a piperidine ring, displayed the best antagonistic activity against FXR with promising cellular potency (IC50 = 0.58 ± 0.27 and 0.127 ± 0.02 μM, respectively). The excellent pharmacokinetic properties make compound 3f the most promising lead identified in this study.

Entities:  

Year:  2019        PMID： 30996787      PMCID： PMC6466555          DOI： 10.1021/acsmedchemlett.8b00534

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


  21 in total

Review 1.  FXR: a promising target for the metabolic syndrome?

Authors:  Bertrand Cariou; Bart Staels
Journal:  Trends Pharmacol Sci       Date:  2007-04-06       Impact factor: 14.819

2.  Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice.

Authors:  Yanqiao Zhang; Florence Ying Lee; Gabriel Barrera; Hans Lee; Charisse Vales; Frank J Gonzalez; Timothy M Willson; Peter A Edwards
Journal:  Proc Natl Acad Sci U S A       Date:  2006-01-12       Impact factor: 11.205

3.  Identification of a nuclear receptor for bile acids.

Authors:  M Makishima; A Y Okamoto; J J Repa; H Tu; R M Learned; A Luk; M V Hull; K D Lustig; D J Mangelsdorf; B Shan
Journal:  Science       Date:  1999-05-21       Impact factor: 47.728

4.  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

5.  Potent arylsulfonamide inhibitors of tumor necrosis factor-alpha converting enzyme able to reduce activated leukocyte cell adhesion molecule shedding in cancer cell models.

Authors:  Elisa Nuti; Francesca Casalini; Stanislava I Avramova; Salvatore Santamaria; Marina Fabbi; Silvano Ferrini; Luciana Marinelli; Valeria La Pietra; Vittorio Limongelli; Ettore Novellino; Giovanni Cercignani; Elisabetta Orlandini; Susanna Nencetti; Armando Rossello
Journal:  J Med Chem       Date:  2010-03-25       Impact factor: 7.446

6.  Structural basis for bile acid binding and activation of the nuclear receptor FXR.

Authors:  Li-Zhi Mi; Srikripa Devarakonda; Joel M Harp; Qing Han; Roberto Pellicciari; Timothy M Willson; Sepideh Khorasanizadeh; Fraydoon Rastinejad
Journal:  Mol Cell       Date:  2003-04       Impact factor: 17.970

7.  Benefit of farnesoid X receptor inhibition in obstructive cholestasis.

Authors:  Catherine Stedman; Christopher Liddle; Sally Coulter; Junichiro Sonoda; Jacqueline G Alvarez; Ronald M Evans; Michael Downes
Journal:  Proc Natl Acad Sci U S A       Date:  2006-07-14       Impact factor: 11.205

Review 8.  The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism.

Authors:  Thierry Claudel; Bart Staels; Folkert Kuipers
Journal:  Arterioscler Thromb Vasc Biol       Date:  2005-07-21       Impact factor: 8.311

9.  FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats.

Authors:  Sabrina Cipriani; Andrea Mencarelli; Giuseppe Palladino; Stefano Fiorucci
Journal:  J Lipid Res       Date:  2009-09-25       Impact factor: 5.922

10.  Ethyl 8-fluoro-6-(3-nitrophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as novel, highly potent, and safe antianxiety agent.

Authors:  Maurizio Anzini; Carlo Braile; Salvatore Valenti; Andrea Cappelli; Salvatore Vomero; Luciana Marinelli; Vittorio Limongelli; Ettore Novellino; Laura Betti; Gino Giannaccini; Antonio Lucacchini; Carla Ghelardini; Monica Norcini; Francesco Makovec; Gianluca Giorgi; R Ian Fryer
Journal:  J Med Chem       Date:  2008-07-19       Impact factor: 7.446
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  7 in total

1.  Regio- and Enantioselective Iridium-Catalyzed Amination of Alkyl-Substituted Allylic Acetates with Secondary Amines.

Authors:  Woo-Ok Jung; Minjin Yoo; Madyson M Migliozzi; Jason R Zbieg; Craig E Stivala; Michael J Krische
Journal:  Org Lett       Date:  2021-12-14       Impact factor: 6.005

2.  Synthesis of a boron-containing amidoxime reagent and its application to synthesize functionalized oxadiazole and quinazolinone derivatives.

Authors:  Bhaskar C Das; Nitesh K Nandwana; Devi P Ojha; Sasmita Das; Todd Evans
Journal:  Tetrahedron Lett       Date:  2022-01-25       Impact factor: 2.032

3.  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

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

Authors:  Naoki Teno; Yusuke Iguchi; Keisuke Oda; Yukiko Yamashita; Arisa Masuda; Ko Fujimori; Mizuho Une; Keigo Gohda
Journal:  ACS Med Chem Lett       Date:  2021-02-24       Impact factor: 4.345

5.  Protein-ligand binding with the coarse-grained Martini model.

Authors:  Paulo C T Souza; Sebastian Thallmair; Paolo Conflitti; Carlos Ramírez-Palacios; Riccardo Alessandri; Stefano Raniolo; Vittorio Limongelli; Siewert J Marrink
Journal:  Nat Commun       Date:  2020-07-24       Impact factor: 14.919

Review 6.  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

7.  A Proteomic Platform Unveils the Brain Glycogen Phosphorylase as a Potential Therapeutic Target for Glioblastoma Multiforme.

Authors:  Giusy Ferraro; Matteo Mozzicafreddo; Roberta Ettari; Lorenzo Corsi; Maria Chiara Monti
Journal:  Int J Mol Sci       Date:  2022-07-25       Impact factor: 6.208
  7 in total

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