title: Discovery of a brain-penetrant S1P₃-sparing direct agonist of the S1P₁ and S1P₅ receptors efficacious at low oral dose.
abstract: 2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RRMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P(5) agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (<1 mg p.o. once daily).
authors.affiliation: Immuno Inflammation Center of Excellence for Drug Discovery, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom. emmanuel.h.demont@gsk.com
authors.forename: Emmanuel H
authors.initials: EH
authors.lastname: Demont
authors.forename: Sandra
authors.initials: S
authors.lastname: Arpino
authors.forename: Rino A
authors.initials: RA
authors.lastname: Bit
authors.forename: Colin A
authors.initials: CA
authors.lastname: Campbell
authors.forename: Nigel
authors.initials: N
authors.lastname: Deeks
authors.forename: Sapna
authors.initials: S
authors.lastname: Desai
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dowell
authors.forename: Pam
authors.initials: P
authors.lastname: Gaskin
authors.forename: James R J
authors.initials: JR
authors.lastname: Gray
authors.forename: Lee A
authors.initials: LA
authors.lastname: Harrison
authors.forename: Andrea
authors.initials: A
authors.lastname: Haynes
authors.forename: Tom D
authors.initials: TD
authors.lastname: Heightman
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Holmes
authors.forename: Philip G
authors.initials: PG
authors.lastname: Humphreys
authors.forename: Umesh
authors.initials: U
authors.lastname: Kumar
authors.forename: Mary A
authors.initials: MA
authors.lastname: Morse
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Osborne
authors.forename: Terry
authors.initials: T
authors.lastname: Panchal
authors.forename: Karen L
authors.initials: KL
authors.lastname: Philpott
authors.forename: Simon
authors.initials: S
authors.lastname: Taylor
authors.forename: Robert
authors.initials: R
authors.lastname: Watson
authors.forename: Robert
authors.initials: R
authors.lastname: Willis
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002463:Cell Membrane Permeability; D004285:Dogs; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D012995:Solubility
chemical_list: C568511:5-(3-(2-(2-hydroxy-1-(hydroxymethyl)ethyl)-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl)-1,2,4-oxadiazol-5-yl)-2-((1-methylethyl)oxy)benzonitrile; D001381:Azepines; D007546:Isoquinolines; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid