title: 4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P1.
abstract: The sphingosine-1-phosphate-1 receptor (S1P1) and its endogenous ligand sphingosine-1-phosphate (S1P) cooperatively regulate lymphocyte trafficking from the lymphatic system. Herein, we disclose 4-methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide (8), an uncommon example of a synthetic S1P1 agonist lacking a polar headgroup, which is shown to effect dramatic reduction of circulating lymphocytes (POC = -78%) in rat 24 h after a single oral dose (1 mg/kg). The excellent potency that 8 exhibits toward S1P1 (EC50 = 0.035 μM, 96% efficacy) and the >100-fold selectivity that it displays against receptor subtypes S1P2-5 suggest that it may serve as a valuable tool to understand the clinical relevance of selective S1P1 agonism.
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Lewis D
authors.initials: LD
authors.lastname: Pennington
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, 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: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Pickrell
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Harrington
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Frohn
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Lanman
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Reed
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Croghan
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lee
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: McElvain
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Xuxia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Fiorino
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Horner
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Henry G
authors.initials: HG
authors.lastname: Morrison
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Arnett
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Wong
authors.affiliation: Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
keywords: Sphingosine-1-phosphate-1 receptor agonist; immunosuppression; multiple sclerosis; peripheral lymphocyte count