Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent sphingosine-1-phosphate receptor subtype-1 agonists

Discovery of two potent and selective sphingosine-1-phosphate receptor agonist chemotypes, alkoxy-phenylamide and alkoxy-phenylimidazole, with potent in vivo oral activity in mouse. In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series o...

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Published in:Bioorganic & medicinal chemistry letters 2009-01, Vol.19 (2), p.369-372
Main Authors: Evindar, Ghotas, Bernier, Sylvie G., Kavarana, Malcolm J., Doyle, Elisabeth, Lorusso, Jeanine, Kelley, Michael S., Halley, Keith, Hutchings, Amy, Wright, Albion D., Saha, Ashis K., Hannig, Gerhard, Morgan, Barry A., Westlin, William F.
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Language:English
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Summary:Discovery of two potent and selective sphingosine-1-phosphate receptor agonist chemotypes, alkoxy-phenylamide and alkoxy-phenylimidazole, with potent in vivo oral activity in mouse. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2008.11.072