Literature DB >> 24900286

Benzofuran Derivatives as Potent, Orally Active S1P1 Receptor Agonists: A Preclinical Lead Molecule for MS.

Ashis K Saha1, Xiang Yu1, Jian Lin1, Mercedes Lobera1, Anurag Sharadendu1, Srinivas Chereku1, Nili Schutz1, Dalia Segal1, Yael Marantz1, Dilara McCauley1, Scot Middleton2, Jerry Siu2, Roland W Bürli3, Janet Buys4, Michelle Horner4, Kevin Salyers5, Michael Schrag5, Hugo M Vargas4, Yang Xu5, Michele McElvain6, Han Xu6.   

Abstract

We have discovered novel benzofuran-based S1P1 agonists with excellent in vitro potency and selectivity. 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl) azetidine-3-carboxylic acid (18) is a potent S1P1 agonist with >1000× selectivity over S1P3. It demonstrated a good in vitro ADME profile and excellent oral bioavailability across species. Dosed orally at 0.3 mg/kg, 18 significantly reduced blood lymphocyte counts 24 h postdose and demonstrated efficacy in a mouse EAE model of relapsing MS.

Entities:  

Keywords:  S1P1; S1P3; Sphingosine-1 phosphate receptor; benzofuran; immunomodulators; lymphopenia; relapsing MS

Year:  2010        PMID： 24900286      PMCID： PMC4017978          DOI： 10.1021/ml100227q

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


  17 in total

1.  PREDICT modeling and in-silico screening for G-protein coupled receptors.

Authors:  Sharon Shacham; Yael Marantz; Shay Bar-Haim; Ori Kalid; Dora Warshaviak; Noa Avisar; Boaz Inbal; Alexander Heifetz; Merav Fichman; Maya Topf; Zvi Naor; Silvia Noiman; Oren M Becker
Journal:  Proteins       Date:  2004-10-01

2.  FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects.

Authors:  Robert Schmouder; Denise Serra; Yibin Wang; John M Kovarik; John DiMarco; Thomas L Hunt; Marie-Claude Bastien
Journal:  J Clin Pharmacol       Date:  2006-08       Impact factor: 3.126

Review 3.  Sphingosine-1-phosphate receptors: zooming in on ligand-induced intracellular trafficking and its functional implications.

Authors:  Dennis Verzijl; Stephan L M Peters; Astrid E Alewijnse
Journal:  Mol Cells       Date:  2010-01-29       Impact factor: 5.034

Review 4.  FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis.

Authors:  Thomas Baumruker; Andreas Billich; Volker Brinkmann
Journal:  Expert Opin Investig Drugs       Date:  2007-03       Impact factor: 6.206

5.  A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.

Authors:  Ludwig Kappos; Ernst-Wilhelm Radue; Paul O'Connor; Chris Polman; Reinhard Hohlfeld; Peter Calabresi; Krzysztof Selmaj; Catherine Agoropoulou; Malgorzata Leyk; Lixin Zhang-Auberson; Pascale Burtin
Journal:  N Engl J Med       Date:  2010-01-20       Impact factor: 91.245

6.  Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate.

Authors:  M Germana Sanna; Jiayu Liao; Euijung Jo; Christopher Alfonso; Min-Young Ahn; Melissa S Peterson; Bill Webb; Sophie Lefebvre; Jerold Chun; Nathanael Gray; Hugh Rosen
Journal:  J Biol Chem       Date:  2004-01-19       Impact factor: 5.157

Review 7.  Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus.

Authors:  Kenji Chiba; Hirofumi Matsuyuki; Yasuhiro Maeda; Kunio Sugahara
Journal:  Cell Mol Immunol       Date:  2006-02       Impact factor: 11.530

Review 8.  FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system.

Authors:  Volker Brinkmann
Journal:  Br J Pharmacol       Date:  2009-10-08       Impact factor: 8.739

Review 9.  Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis.

Authors:  Jerold Chun; Hans-Peter Hartung
Journal:  Clin Neuropharmacol       Date:  2010 Mar-Apr       Impact factor: 1.592

10.  Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes.

Authors:  M Forrest; S-Y Sun; R Hajdu; J Bergstrom; D Card; G Doherty; J Hale; C Keohane; C Meyers; J Milligan; S Mills; N Nomura; H Rosen; M Rosenbach; G-J Shei; I I Singer; M Tian; S West; V White; J Xie; R L Proia; S Mandala
Journal:  J Pharmacol Exp Ther       Date:  2004-01-27       Impact factor: 4.030
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  3 in total

1.  Discovery of a Selective S1P1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate.

Authors:  Emmanuel H Demont; Benjamin I Andrews; Rino A Bit; Colin A Campbell; Jason W B Cooke; Nigel Deeks; Sapna Desai; Simon J Dowell; Pam Gaskin; James R J Gray; Andrea Haynes; Duncan S Holmes; Umesh Kumar; Mary A Morse; Greg J Osborne; Terry Panchal; Bela Patel; Alcide Perboni; Simon Taylor; Robert Watson; Jason Witherington; Robert Willis
Journal:  ACS Med Chem Lett       Date:  2011-03-24       Impact factor: 4.345

Review 2.  Integrating the puzzle pieces: the current atomistic picture of phospholipid-G protein coupled receptor interactions.

Authors:  Abby L Parrill; Gabor Tigyi
Journal:  Biochim Biophys Acta       Date:  2012-09-12

3.  The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P₁) and hypertension (S1P₃) in rat.

Authors:  Ryan M Fryer; Akalushi Muthukumarana; Paul C Harrison; Suzanne Nodop Mazurek; Rong Rhonda Chen; Kyle E Harrington; Roger M Dinallo; Joshua C Horan; Lori Patnaude; Louise K Modis; Glenn A Reinhart
Journal:  PLoS One       Date:  2012-12-28       Impact factor: 3.240
  3 in total

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