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Hugh Rosen - One of the best experts on this subject based on the ideXlab platform.
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Sphingosine-1-Phosphate Receptor Agonism Reduces Bordetella pertussis–mediated Lung Pathology
The Journal of infectious diseases, 2014Co-Authors: Ciaran Skerry, Hugh Rosen, Karen M. Scanlon, Nicholas H. CarbonettiAbstract:Recent pertussis resurgence represents a major public health concern. Currently, there are no effective treatments for critical pertussis in infants. Recent data have demonstrated the potential of Sphingosine-1-Phosphate Receptor (S1PR) agonism in the treatment of infectious diseases. We used the murine Bordetella pertussis model to test the hypothesis that treatment with S1PR agonist AAL-R reduces pulmonary inflammation during infection. AAL-R treatment resulted in reduced expression of inflammatory cytokines and chemokines and attenuated lung pathology in infected mice. These results demonstrate a role for Sphingosine-1-Phosphate (S1P) signaling in B. pertussis-mediated pathology and highlight the possibility of host-targeted therapy for pertussis.
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Sphingosine kinase 2 prevents the nuclear translocation of sphingosine 1-phosphate Receptor-2 and tyrosine 416 phosphorylated c-Src and increases estrogen Receptor negative MDA-MB-231 breast cancer cell growth : the role of sphingosine 1-phosphate re
Cellular signalling, 2014Co-Authors: Jan Ohotski, Hugh Rosen, Robert Bittman, Susan Pyne, Nigel J. PyneAbstract:We demonstrate that pre-treatment of estrogen Receptor negative MDA-MB-231 breast cancer cells containing ectopically expressed HA-tagged sphingosine 1-phosphate Receptor-2 (S1P2) with the sphingosine kinase 1/2 inhibitor SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) or the sphingosine kinase 2 selective inhibitor (R)-FTY720 methyl ether (ROMe) or sphingosine kinase 2 siRNA induced the translocation of HA-tagged S1P2 and Y416 phosphorylated c-Src to the nucleus of these cells. This is associated with reduced growth of HA-tagged S1P2 over-expressing MDA-MB-231 cells. Treatment of HA-S1P2 over-expressing MDA-MB-231 cells with the sphingosine 1-phosphate Receptor-4 (S1P4) antagonist CYM50367 or with S1P4 siRNA also promoted nuclear translocation of HA-tagged S1P2. These findings identify for the first time a signaling pathway in which sphingosine 1-phosphate formed by sphingosine kinase 2 binds to S1P4 to prevent nuclear translocation of S1P2 and thereby promote the growth of estrogen Receptor negative breast cancer cells.
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Modulators of the Sphingosine 1-phosphate Receptor 1.
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Mariangela Urbano, Miguel Guerrero, Hugh Rosen, Edward RobertsAbstract:The Sphingosine 1-phosphate Receptor (S1P-R) signaling system has proven to be of biological and medical importance in autoimmune settings. S1P1-R is a validated drug target for multiple sclerosis (MS) for which FTY720 (Fingolimod), a S1P1,3-5-R pan-agonist, was recently approved as the first orally active drug for the treatment of relapsing-remitting MS. Transient bradycardia and long half-life are the FTY720 critical pitfalls. This review provides the latest advances on next-generation S1P1-R modulators from 2012 up to date, with an overview of the chemical structures, structure-activity relationships, and relevant biological and clinical properties.
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Sphingosine 1-Phosphate Receptor 1 (S1P1) Upregulation and Amelioration of Experimental Autoimmune Encephalomyelitis by an S1P1 Antagonist
Molecular pharmacology, 2012Co-Authors: Stuart M. Cahalan, Nora B. Leaf, Miguel Guerrero, Edward Roberts, Pedro J. Gonzalez-cabrera, Nhan Nguyen, Elizabeth A. George Cisar, Steven J. Brown, Hugh RosenAbstract:Sphingosine 1-phosphate Receptor 1 (S1P1) is a G protein–coupled Receptor that is critical for proper lymphocyte development and recirculation. Agonists to S1P1 are currently in use clinically for the treatment of multiple sclerosis, and these drugs may act on both S1P1 expressed on lymphocytes and S1P1 expressed within the central nervous system. Agonists to S1P1 and deficiency in S1P1 both cause lymphocyte sequestration in the lymph nodes. In the present study, we show that S1P1 antagonism induces lymphocyte sequestration in the lymph nodes similar to that observed with S1P1 agonists while upregulating S1P1 on lymphocytes and endothelial cells. Additionally, we show that S1P1 antagonism reverses experimental autoimmune encephalomyelitis in mice without acting on S1P1 expressed within the central nervous system, demonstrating that lymphocyte sequestration via S1P1 antagonism is sufficient to alleviate autoimmune pathology.
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ACCELERATED COMMUNICATION Sphingosine 1-Phosphate Receptor 1 (S1P1) Upregulation and Amelioration of Experimental Autoimmune Encephalomyelitis by an S1P1 Antagonist s
2012Co-Authors: Stuart M. Cahalan, Nora B. Leaf, Miguel Guerrero, Edward Roberts, Pedro J. Gonzalez-cabrera, Nhan Nguyen, Elizabeth A. George Cisar, Steven J. Brown, Hugh RosenAbstract:Sphingosine 1-phosphate Receptor 1 (S1P1) is a G protein– coupled Receptor that is critical for proper lymphocyte de-velopment and recirculation. Agonists to S1P1 are currently in use clinically for the treatment of multiple sclerosis, and these drugs may act on both S1P1 expressed on lymphocytes and S1P1 expressed within the central nervous system. Agonists to S1P1 and deficiency in S1P1 both cause lymphocyte seques-tration in the lymph nodes. In the present study, we show that S1P1 antagonism induces lymphocyte sequestration in the lymph nodes similar to that observed with S1P1 agonists while upregulating S1P1 on lymphocytes and endothelial cells. Additionally, we show that S1P1 antagonism reverses experi-mental autoimmune encephalomyelitis in mice without acting on S1P1 expressed within the central nervous system, demonstrat-ing that lymphocyte sequestration via S1P1 antagonism is sufficient to alleviate autoimmune pathology
Ghotas Evindar - One of the best experts on this subject based on the ideXlab platform.
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Exploring amino acids derivatives as potent, selective, and direct agonists of Sphingosine-1-Phosphate Receptor subtype-1.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Elisabeth Doyle, Jeanine Lorusso, Hongfeng Deng, Barry A. Morgan, William F. WestlinAbstract:In the quest to discover a potent and selective class of direct agonists to the Sphingosine-1-Phosphate Receptor, we explored the carboxylate functional group as a replacement to previously reported lead phosphates. This has led to the discovery of potent and selective direct agonists with moderate to substantial in vivo lymphopenia. The previously reported selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) in the phenylamide and phenylimidazole scaffolds were crucial to obtaining selectivity for S1P Receptor subtype 1 over 3.
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Exploration of amino alcohol derivatives as novel, potent, and highly selective Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Ashis K. Saha, Alexander L. Satz, Heather S. Blanchette, Gerhard Hannig, Barry A. MorganAbstract:In pursuit of a potent and highly selective Sphingosine-1-Phosphate Receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P Receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.
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Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Keith Halley, Amy Hutchings, Alexander L. Satz, Nazbeh Taghizadeh, Michael KelleyAbstract:In pursuit of potent and selective Sphingosine-1-Phosphate Receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.
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Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Michael Kelley, Keith Halley, Amy Hutchings, Albion D. Wright, Ashis K. SahaAbstract:In the design of potent and selective Sphingosine-1-Phosphate Receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P Receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.
Jeanine Lorusso - One of the best experts on this subject based on the ideXlab platform.
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Exploring amino acids derivatives as potent, selective, and direct agonists of Sphingosine-1-Phosphate Receptor subtype-1.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Elisabeth Doyle, Jeanine Lorusso, Hongfeng Deng, Barry A. Morgan, William F. WestlinAbstract:In the quest to discover a potent and selective class of direct agonists to the Sphingosine-1-Phosphate Receptor, we explored the carboxylate functional group as a replacement to previously reported lead phosphates. This has led to the discovery of potent and selective direct agonists with moderate to substantial in vivo lymphopenia. The previously reported selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) in the phenylamide and phenylimidazole scaffolds were crucial to obtaining selectivity for S1P Receptor subtype 1 over 3.
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Exploration of amino alcohol derivatives as novel, potent, and highly selective Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Ashis K. Saha, Alexander L. Satz, Heather S. Blanchette, Gerhard Hannig, Barry A. MorganAbstract:In pursuit of a potent and highly selective Sphingosine-1-Phosphate Receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P Receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.
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Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Keith Halley, Amy Hutchings, Alexander L. Satz, Nazbeh Taghizadeh, Michael KelleyAbstract:In pursuit of potent and selective Sphingosine-1-Phosphate Receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.
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Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Michael Kelley, Keith Halley, Amy Hutchings, Albion D. Wright, Ashis K. SahaAbstract:In the design of potent and selective Sphingosine-1-Phosphate Receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P Receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.
Sylvie G. Bernier - One of the best experts on this subject based on the ideXlab platform.
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Exploring amino acids derivatives as potent, selective, and direct agonists of Sphingosine-1-Phosphate Receptor subtype-1.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Elisabeth Doyle, Jeanine Lorusso, Hongfeng Deng, Barry A. Morgan, William F. WestlinAbstract:In the quest to discover a potent and selective class of direct agonists to the Sphingosine-1-Phosphate Receptor, we explored the carboxylate functional group as a replacement to previously reported lead phosphates. This has led to the discovery of potent and selective direct agonists with moderate to substantial in vivo lymphopenia. The previously reported selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) in the phenylamide and phenylimidazole scaffolds were crucial to obtaining selectivity for S1P Receptor subtype 1 over 3.
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Exploration of amino alcohol derivatives as novel, potent, and highly selective Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Ashis K. Saha, Alexander L. Satz, Heather S. Blanchette, Gerhard Hannig, Barry A. MorganAbstract:In pursuit of a potent and highly selective Sphingosine-1-Phosphate Receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P Receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.
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Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Keith Halley, Amy Hutchings, Alexander L. Satz, Nazbeh Taghizadeh, Michael KelleyAbstract:In pursuit of potent and selective Sphingosine-1-Phosphate Receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.
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Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Michael Kelley, Keith Halley, Amy Hutchings, Albion D. Wright, Ashis K. SahaAbstract:In the design of potent and selective Sphingosine-1-Phosphate Receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P Receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.
Elisabeth Doyle - One of the best experts on this subject based on the ideXlab platform.
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Exploring amino acids derivatives as potent, selective, and direct agonists of Sphingosine-1-Phosphate Receptor subtype-1.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Elisabeth Doyle, Jeanine Lorusso, Hongfeng Deng, Barry A. Morgan, William F. WestlinAbstract:In the quest to discover a potent and selective class of direct agonists to the Sphingosine-1-Phosphate Receptor, we explored the carboxylate functional group as a replacement to previously reported lead phosphates. This has led to the discovery of potent and selective direct agonists with moderate to substantial in vivo lymphopenia. The previously reported selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) in the phenylamide and phenylimidazole scaffolds were crucial to obtaining selectivity for S1P Receptor subtype 1 over 3.
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Exploration of amino alcohol derivatives as novel, potent, and highly selective Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Ashis K. Saha, Alexander L. Satz, Heather S. Blanchette, Gerhard Hannig, Barry A. MorganAbstract:In pursuit of a potent and highly selective Sphingosine-1-Phosphate Receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P Receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.
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Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Keith Halley, Amy Hutchings, Alexander L. Satz, Nazbeh Taghizadeh, Michael KelleyAbstract:In pursuit of potent and selective Sphingosine-1-Phosphate Receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia.
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Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent Sphingosine-1-Phosphate Receptor subtype-1 agonists.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Ghotas Evindar, Sylvie G. Bernier, Malcolm J. Kavarana, Elisabeth Doyle, Jeanine Lorusso, Michael Kelley, Keith Halley, Amy Hutchings, Albion D. Wright, Ashis K. SahaAbstract:In the design of potent and selective Sphingosine-1-Phosphate Receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P Receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.