Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective sphingosine-1-phosphate receptor subtype-1 agonists.
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.
Evindar
Ghotas
G
Department of Medicinal Chemistry, Praecis Pharmaceuticals Incorporated, Waltham, MA 02451, United States. ghotas.x.evindar@gsk.com
Satz
Alexander L
AL
Bernier
Sylvie G
SG
Kavarana
Malcolm J
MJ
Doyle
Elisabeth
E
Lorusso
Jeanine
J
Taghizadeh
Nazbeh
N
Halley
Keith
K
Hutchings
Amy
A
Kelley
Michael S
MS
Wright
Albion D
AD
Saha
Ashis K
AK
Hannig
Gerhard
G
Morgan
Barry A
BA
Westlin
William F
WF
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000068876:Fingolimod Hydrochloride; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D011409:Propylene Glycols / Q000737:chemistry / Q000494:pharmacology; D021122:Protein Subunits / Q000819:agonists / Q000502:physiology; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
D000577:Amides; D007093:Imidazoles; D011409:Propylene Glycols; D021122:Protein Subunits; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine