Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent sphingosine-1-phosphate receptor subtype-1 agonists.
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.
Evindar
Ghotas
G
Department of Medicinal Chemistry, Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451, USA. ghotas.x.evindar@gsk.com
Bernier
Sylvie G
SG
Kavarana
Malcolm J
MJ
Doyle
Elisabeth
E
Lorusso
Jeanine
J
Kelley
Michael S
MS
Halley
Keith
K
Hutchings
Amy
A
Wright
Albion D
AD
Saha
Ashis K
AK
Hannig
Gerhard
G
Morgan
Barry A
BA
Westlin
William F
WF
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
D000577:Amides; D007093:Imidazoles; D049349:Receptors, Lysosphingolipid