title: Benzofuran Derivatives as Potent, Orally Active S1P1 Receptor Agonists: A Preclinical Lead Molecule for MS.
abstract: We have discovered novel benzofuran-based S1P1 agonists with excellent in vitro potency and selectivity. 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl) azetidine-3-carboxylic acid (18) is a potent S1P1 agonist with >1000× selectivity over S1P3. It demonstrated a good in vitro ADME profile and excellent oral bioavailability across species. Dosed orally at 0.3 mg/kg, 18 significantly reduced blood lymphocyte counts 24 h postdose and demonstrated efficacy in a mouse EAE model of relapsing MS.
authors.affiliation: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Ashis K
authors.initials: AK
authors.lastname: Saha
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: 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: 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: Srinivas
authors.initials: S
authors.lastname: Chereku
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: Dalia
authors.initials: D
authors.lastname: Segal
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: EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
authors.forename: Dilara
authors.initials: D
authors.lastname: McCauley
authors.affiliation: Inflammation Research.
authors.forename: Scot
authors.initials: S
authors.lastname: Middleton
authors.affiliation: Inflammation Research.
authors.forename: Jerry
authors.initials: J
authors.lastname: Siu
authors.affiliation: Departments of Medicinal Chemistry.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Bürli
authors.affiliation: Comparative Biology and Safety Sciences.
authors.forename: Janet
authors.initials: J
authors.lastname: Buys
authors.affiliation: Comparative Biology and Safety Sciences.
authors.forename: Michelle
authors.initials: M
authors.lastname: Horner
authors.affiliation: Pharmacokinetics and Drug Metabolism.
authors.forename: Kevin
authors.initials: K
authors.lastname: Salyers
authors.affiliation: Pharmacokinetics and Drug Metabolism.
authors.forename: Michael
authors.initials: M
authors.lastname: Schrag
authors.affiliation: Comparative Biology and Safety Sciences.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
authors.affiliation: Pharmacokinetics and Drug Metabolism.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Molecular Pharmacology.
authors.forename: Michele
authors.initials: M
authors.lastname: McElvain
authors.affiliation: Molecular Pharmacology.
authors.forename: Han
authors.initials: H
authors.lastname: Xu
keywords: S1P1; S1P3; Sphingosine-1 phosphate receptor; benzofuran; immunomodulators; lymphopenia; relapsing MS