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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 2; pp. 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.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.01.2009; Elsevier
• Subjects: Alkoxy-phenylamides; Alkoxy-phenylimidazoles; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Biological and medical sciences; Dose-Response Relationship, Drug; EDG1; FTY-720; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Immunomodulators; Medical sciences; Mice; Pharmacology. Drug treatments; Receptors, Lysosphingolipid - agonists; S1P; S1P agonist; Sphingosine-1-phosphate; Structure-Activity Relationship; S1P; FTY-720; Sphingosine-1-phosphate; EDG1; Alkoxy-phenylimidazoles; Alkoxy-phenylamides; S1P agonist; Imidazole derivatives; Agonist; Structure activity relation; Chemical synthesis; Lymphocytopenia; Human; Aminoalcohol; Ether; Fingolimod; Aminoamide; Aliphatic compound; Rodentia; Benzene derivatives; Oral administration; In vitro; Immunomodulator; In vivo; α-Aminoacid; Vertebrata; Mammalia; Mouse; Animal; Affinity; SIP
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.11.072

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.