title: Optimization of a Potent, Orally Active S1P1 Agonist Containing a Quinolinone Core.
abstract: The optimization of a series of S1P1 agonists with limited activity against S1P3 is reported. A polar headgroup was used to improve the physicochemical and pharmacokinetic parameters of lead quinolinone 6. When dosed orally at 1 and 3 mg/kg, the azahydroxymethyl analogue 22 achieved statistically significant lowering of circulating blood lymphocytes 24 h postdose. In rats, a dose-proportional increase in exposure was measured when 22 was dosed orally at 2 and 100 mg/kg.
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Harrington
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Croghan
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Frohn
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Lanman
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Lewis D
authors.initials: LD
authors.lastname: Pennington
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Pickrell
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Reed
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Kelvin K C
authors.initials: KK
authors.lastname: Sham
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tasker
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Arnett
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Fiorino
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lee
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: McElvain
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Henry G
authors.initials: HG
authors.lastname: Morrison
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Xuxia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Wong
authors.affiliation: Chemistry Research and Discovery, Inflammation Research, Molecular Structure, HTS and Molecular Pharmacology, Pharmaceutics, and Pharmacokinetics and Drug Metabolism, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
keywords: S1P1; Sphingosine-1-phosphate receptor; agonist; multiple sclerosis