title: Isoform-selective thiazolo[5,4-b]pyridine S1P1 agonists possessing acyclic amino carboxylate head-groups.
abstract: Replacement of the azetidine carboxylate of an S1P(1) agonist development candidate, AMG 369, with a range of acyclic head-groups led to the identification of a novel, S1P(3)-sparing S1P(1) agonist, (-)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid (8c), which possessed good in vivo efficacy and pharmacokinetic properties. A 0.3mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24h post-dosing in female Lewis rats.
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States. areed@amgen.com
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Reed
authors.forename: Brian A
authors.initials: BA
authors.lastname: Lanman
authors.forename: Susana
authors.initials: S
authors.lastname: Neira
authors.forename: Paul E
authors.initials: PE
authors.lastname: Harrington
authors.forename: Kelvin K C
authors.initials: KK
authors.lastname: Sham
authors.forename: Mike
authors.initials: M
authors.lastname: Frohn
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Pickrell
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
authors.forename: Anu
authors.initials: A
authors.lastname: Gore
authors.forename: Mike
authors.initials: M
authors.lastname: Fiorino
authors.forename: Andrea
authors.initials: A
authors.lastname: Itano
authors.forename: Michele
authors.initials: M
authors.lastname: McElvain
authors.forename: Scot
authors.initials: S
authors.lastname: Middleton
authors.forename: Henry
authors.initials: H
authors.lastname: Morrison
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Wong
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000737:chemistry*; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry*; D003500:Cyclization; D005260:Female; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C572311:2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo(5,4-b)pyridin-2-yl)phenyl)-2-methylbutanoic acid; D000588:Amines; D002264:Carboxylic Acids; D020033:Protein Isoforms; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; C023666:pyridine