Literature DB >> 24900374

Optimization of a Potent, Orally Active S1P1 Agonist Containing a Quinolinone Core.

Paul E Harrington1, Michael D Croghan1, Christopher Fotsch1, Mike Frohn1, Brian A Lanman1, Lewis D Pennington1, Alexander J Pickrell1, Anthony B Reed1, Kelvin K C Sham1, Andrew Tasker1, Heather A Arnett1, Michael Fiorino1, Matthew R Lee1, Michele McElvain1, Henry G Morrison1, Han Xu1, Yang Xu1, Xuxia Zhang1, Min Wong1, Victor J Cee1.   

Abstract

The optimization of a series of S1P1 agonists with limited activity against S1P3 is reported. A polar headgroup was used to improve the physicochemical and pharmacokinetic parameters of lead quinolinone 6. When dosed orally at 1 and 3 mg/kg, the azahydroxymethyl analogue 22 achieved statistically significant lowering of circulating blood lymphocytes 24 h postdose. In rats, a dose-proportional increase in exposure was measured when 22 was dosed orally at 2 and 100 mg/kg.

Entities:  

Keywords:  S1P1; Sphingosine-1-phosphate receptor; agonist; multiple sclerosis

Year:  2011        PMID： 24900374      PMCID： PMC4025730          DOI： 10.1021/ml200252b

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


  20 in total

1.  Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.

Authors:  Suzanne Mandala; Richard Hajdu; James Bergstrom; Elizabeth Quackenbush; Jenny Xie; James Milligan; Rosemary Thornton; Gan-Ju Shei; Deborah Card; CarolAnn Keohane; Mark Rosenbach; Jeffrey Hale; Christopher L Lynch; Kathleen Rupprecht; William Parsons; Hugh Rosen
Journal:  Science       Date:  2002-03-28       Impact factor: 47.728

Review 2.  Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis.

Authors:  Volker Brinkmann; Andreas Billich; Thomas Baumruker; Peter Heining; Robert Schmouder; Gordon Francis; Shreeram Aradhye; Pascale Burtin
Journal:  Nat Rev Drug Discov       Date:  2010-10-29       Impact factor: 84.694

3.  Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor.

Authors:  Myat Lin Oo; Shobha Thangada; Ming-Tao Wu; Catherine H Liu; Timothy L Macdonald; Kevin R Lynch; Chen-Yong Lin; Timothy Hla
Journal:  J Biol Chem       Date:  2007-01-21       Impact factor: 5.157

4.  FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing.

Authors:  K Chiba; Y Yanagawa; Y Masubuchi; H Kataoka; T Kawaguchi; M Ohtsuki; Y Hoshino
Journal:  J Immunol       Date:  1998-05-15       Impact factor: 5.422

5.  Quinolinone-based agonists of S1P₁: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.

Authors:  Lewis D Pennington; Michael D Croghan; Kelvin K C Sham; Alexander J Pickrell; Paul E Harrington; Michael J Frohn; Brian A Lanman; Anthony B Reed; Matthew R Lee; Han Xu; Michele McElvain; Yang Xu; Xuxia Zhang; Michael Fiorino; Michelle Horner; Henry G Morrison; Heather A Arnett; Christopher Fotsch; Andrew S Tasker; Min Wong; Victor J Cee
Journal:  Bioorg Med Chem Lett       Date:  2011-11-04       Impact factor: 2.823

6.  4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P1.

Authors:  Lewis D Pennington; Kelvin K C Sham; Alexander J Pickrell; Paul E Harrington; Michael J Frohn; Brian A Lanman; Anthony B Reed; Michael D Croghan; Matthew R Lee; Han Xu; Michele McElvain; Yang Xu; Xuxia Zhang; Michael Fiorino; Michelle Horner; Henry G Morrison; Heather A Arnett; Christopher Fotsch; Min Wong; Victor J Cee
Journal:  ACS Med Chem Lett       Date:  2011-07-29       Impact factor: 4.345

Review 7.  Multiple sclerosis - candidate mechanisms underlying CNS atrophy.

Authors:  Volker Siffrin; Johannes Vogt; Helena Radbruch; Robert Nitsch; Frauke Zipp
Journal:  Trends Neurosci       Date:  2010-02-12       Impact factor: 13.837

Review 8.  The outs and the ins of sphingosine-1-phosphate in immunity.

Authors:  Sarah Spiegel; Sheldon Milstien
Journal:  Nat Rev Immunol       Date:  2011-05-06       Impact factor: 53.106

9.  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

10.  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
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  3 in total

Review 1.  Modulators of the Sphingosine 1-phosphate receptor 1.

Authors:  Mariangela Urbano; Miguel Guerrero; Hugh Rosen; Edward Roberts
Journal:  Bioorg Med Chem Lett       Date:  2013-09-29       Impact factor: 2.823

2.  Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator.

Authors:  Shifeng Pan; Nathanael S Gray; Wenqi Gao; Yuan Mi; Yi Fan; Xing Wang; Tove Tuntland; Jianwei Che; Sophie Lefebvre; Yu Chen; Alan Chu; Klaus Hinterding; Anne Gardin; Peter End; Peter Heining; Christian Bruns; Nigel G Cooke; Barbara Nuesslein-Hildesheim
Journal:  ACS Med Chem Lett       Date:  2013-01-04       Impact factor: 4.345

Review 3.  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 in total

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