title: Discovery of a Potent, S1P3-Sparing Benzothiazole Agonist of Sphingosine-1-Phosphate Receptor 1 (S1P1).
abstract: Optimization of a benzofuranyl S1P1 agonist lead compound (3) led to the discovery of 1-(3-fluoro-4-(5-(2-fluorobenzyl)benzo[d]thiazol-2-yl)benzyl)azetidine-3-carboxylic acid (14), a potent S1P1 agonist with minimal activity at S1P3. Dosed orally at 0.3 mg/kg, 14 significantly reduced blood lymphocyte counts 24 h postdose and attenuated a delayed type hypersensitivity (DTH) response to antigen challenge.
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: Victor J
authors.initials: VJ
authors.lastname: Cee
authors.affiliation: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Srinivasa R
authors.initials: SR
authors.lastname: Cheruku
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: Jennifer
authors.initials: J
authors.lastname: Golden
authors.affiliation: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.affiliation: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Lobera
authors.affiliation: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Yael
authors.initials: Y
authors.lastname: Marantz
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Muller
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Susana C
authors.initials: SC
authors.lastname: Neira
authors.affiliation: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Pickrell
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: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Nili
authors.initials: N
authors.lastname: Schutz
authors.affiliation: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Anurag
authors.initials: A
authors.lastname: Sharadendu
authors.affiliation: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yu
authors.affiliation: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Zhaoda
authors.initials: Z
authors.lastname: Zhang
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: Mike
authors.initials: M
authors.lastname: Fiorino
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: 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: 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: 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: Roland W
authors.initials: RW
authors.lastname: Bürli
keywords: S1P1; Sphingosine-1-phosphate receptor; agonist; inflammation; lymphocyte