title: Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P1 and S1P5.
abstract: The optimization of a series of thiazolopyridine S1P1 agonists with limited activity at the S1P3 receptor is reported. These efforts resulted in the discovery of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid (5d, AMG 369), a potent dual S1P1/S1P5 agonist with limited activity at S1P3 and no activity at S1P2/S1P4. Dosed orally at 0.1 mg/kg, 5d is shown to reduce blood lymphocyte counts 24 h postdose and delay the onset and reduce the severity of experimental autoimmune encephalomyelitis in rat.
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Frohn
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Lanman
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Golden
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Kristine
authors.initials: K
authors.lastname: Muller
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Susana
authors.initials: S
authors.lastname: Neira
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Pickrell
authors.affiliation: Amgen Inc., 1201 Amgen Court West, Seattle, Washington 98119, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Arnett
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Janet
authors.initials: J
authors.lastname: Buys
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Anu
authors.initials: A
authors.lastname: Gore
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Fiorino
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Horner
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Itano
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Matt R
authors.initials: MR
authors.lastname: Lee
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: McElvain
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Scot
authors.initials: S
authors.lastname: Middleton
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Schrag
authors.affiliation: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Dalia
authors.initials: D
authors.lastname: Rivenzon-Segal
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Xuxia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Siu
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Wong
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Bürli
keywords: S1P1; Sphingosine-1-phosphate receptor; inflammation; lymphocyte; multiple sclerosis