title: Optimization of sphingosine-1-phosphate-1 receptor agonists: effects of acidic, basic, and zwitterionic chemotypes on pharmacokinetic and pharmacodynamic profiles.
abstract: The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.
authors.affiliation: Neurology Center of Excellence for Drug Discovery, GlaxoSmithKline , New Frontiers Science Park, Harlow CM19 5AW, U.K.
authors.forename: John
authors.initials: J
authors.lastname: Skidmore
authors.forename: Jag
authors.initials: J
authors.lastname: Heer
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Norton
authors.forename: Sally
authors.initials: S
authors.lastname: Redshaw
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sweeting
authors.forename: David
authors.initials: D
authors.lastname: Hurst
authors.forename: Andrew
authors.initials: A
authors.lastname: Cridland
authors.forename: David
authors.initials: D
authors.lastname: Vesey
authors.forename: Ian
authors.initials: I
authors.lastname: Wall
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ahmed
authors.forename: Dean
authors.initials: D
authors.lastname: Rivers
authors.forename: James
authors.initials: J
authors.lastname: Myatt
authors.forename: Gerard
authors.initials: G
authors.lastname: Giblin
authors.forename: Karen
authors.initials: K
authors.lastname: Philpott
authors.forename: Umesh
authors.initials: U
authors.lastname: Kumar
authors.forename: Alexander
authors.initials: A
authors.lastname: Stevens
authors.forename: Rino A
authors.initials: RA
authors.lastname: Bit
authors.forename: Andrea
authors.initials: A
authors.lastname: Haynes
authors.forename: Simon
authors.initials: S
authors.lastname: Taylor
authors.forename: Robert
authors.initials: R
authors.lastname: Watson
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Demont
authors.forename: Tom D
authors.initials: TD
authors.lastname: Heightman
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry*; D002478:Cells, Cultured; D006571:Heterocyclic Compounds / Q000737:chemistry*; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D006571:Heterocyclic Compounds; D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid