title: Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective sphingosine-1-phosphate receptor subtype-1 agonists.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Praecis Pharmaceuticals Incorporated, Waltham, MA 02451, United States. ghotas.x.evindar@gsk.com
authors.forename: Ghotas
authors.initials: G
authors.lastname: Evindar
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Satz
authors.forename: Sylvie G
authors.initials: SG
authors.lastname: Bernier
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Kavarana
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Doyle
authors.forename: Jeanine
authors.initials: J
authors.lastname: Lorusso
authors.forename: Nazbeh
authors.initials: N
authors.lastname: Taghizadeh
authors.forename: Keith
authors.initials: K
authors.lastname: Halley
authors.forename: Amy
authors.initials: A
authors.lastname: Hutchings
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kelley
authors.forename: Albion D
authors.initials: AD
authors.lastname: Wright
authors.forename: Ashis K
authors.initials: AK
authors.lastname: Saha
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hannig
authors.forename: Barry A
authors.initials: BA
authors.lastname: Morgan
authors.forename: William F
authors.initials: WF
authors.lastname: Westlin
mesh_terms: 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
chemical_list: D000577:Amides; D007093:Imidazoles; D011409:Propylene Glycols; D021122:Protein Subunits; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine