Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator
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 Graham Cooke,Barbara Nuesslein-Hildesheim +17 more
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A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point, which has recently completed phase 2 clinical trials in patients with relapsing-remitting multiple sclerosis.Abstract:
A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure–activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing–remitting multiple sclerosis.read more
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Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas
Yu Zhou,Jiang Wang,Zhanni Gu,Shuni Wang,Wei Zhu,José Luis Aceña,Vadim A. Soloshonok,Kunisuke Izawa,Hong Liu +8 more
TL;DR: Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas is presented.
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Natural product and natural product derived drugs in clinical trials
TL;DR: The next few years will be critical for NP-driven lead discovery, and a concerted effort is required to identify new biologically active pharmacophores and to progress these and existing compounds through pre-clinical drug development into clinical trials.
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Can We Design a Nogo Receptor-Dependent Cellular Therapy to Target MS?
TL;DR: The current review outlines novel means to achieve neurorepair with biologicals that may be directed to sites of active demyelination and the Nogo-A receptor-dependent signaling mechanism, which has raised considerable interest in neurological disease paradigms.
Journal ArticleDOI
Fluorine-containing drugs approved by the FDA in 2019
Haibo Mei,Attila Márió Remete,Yupiao Zou,Hiroki Moriwaki,Santos Fustero,Loránd Kiss,Vadim A. Soloshonok,Vadim A. Soloshonok,Jianlin Han +8 more
TL;DR: Eleven new fluorine-containing FDA-approved drugs have been profiled and details of their discovery and preparation are discussed, including four examples of aromatic fluorine, three aromatic CF3 group, three aliphatic CF3 and one compound with aromaticCF3O group.
Journal ArticleDOI
Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation.
Veit Rothhammer,Jessica E. Kenison,Emily C. Tjon,Maisa C. Takenaka,Kalil Alves de Lima,Davis M. Borucki,Chun-Cheih Chao,Annabel Wilz,Manon Blain,Luke M. Healy,Jack P. Antel,Francisco J. Quintana,Francisco J. Quintana +12 more
TL;DR: It is demonstrated that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS.
References
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Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1
Mehrdad Matloubian,Charles G. Lo,Guy Cinamon,Matthew J. Lesneski,Ying Xu,Volker Brinkmann,Maria L. Allende,Richard L. Proia,Jason G. Cyster +8 more
TL;DR: It is established that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists.
Suzanne M. Mandala,Richard Hajdu,James D. Bergstrom,Elizabeth J. Quackenbush,Jenny Xie,James A. Milligan,Rosemary A. Thornton,Gan-Ju Shei,Deborah Card,CarolAnn Keohane,Mark Rosenbach,Jeffrey J. Hale,Christopher L. Lynch,Kathleen M. Rupprecht,William H. Parsons,Hugh Rosen +15 more
TL;DR: It is shown that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolites of the immunosuppressive agent FTY720.
Journal ArticleDOI
The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
Volker Brinkmann,Michael Davis,Christopher E. Heise,R. Albert,Sylvain Cottens,Robert Paul Hof,Christian Bruns,Eva Prieschl,Thomas Baumruker,Peter Hiestand,Carolyn An Foster,Markus Zollinger,Kevin R. Lynch +12 more
TL;DR: The results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.
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Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis
Volker Brinkmann,Andreas Billich,Thomas Baumruker,Peter Heining,Robert Schmouder,Gordon Francis,Shreeram Aradhye,Pascale Burtin +7 more
TL;DR: The discovery and development of fingolimod is described, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.
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Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs
TL;DR: The steps associated with the initiation of adaptive immune responses in secondary lymphoid organs are reviewed, highlighting the roles of chemokines and S1P.