title: Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders.
abstract: During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.
authors.affiliation: Lexicon Pharmaceuticals, Princeton, New Jersey, USA. jbagdanoff@lexpharma.com
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Bagdanoff
authors.forename: Michael S
authors.initials: MS
authors.lastname: Donoviel
authors.forename: Amr
authors.initials: A
authors.lastname: Nouraldeen
authors.forename: James
authors.initials: J
authors.lastname: Tarver
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Fu
authors.forename: Marianne
authors.initials: M
authors.lastname: Carlsen
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Jessop
authors.forename: Haiming
authors.initials: H
authors.lastname: Zhang
authors.forename: Jill
authors.initials: J
authors.lastname: Hazelwood
authors.forename: Huy
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authors.lastname: Nguyen
authors.forename: Simon D P
authors.initials: SD
authors.lastname: Baugh
authors.forename: Michael
authors.initials: M
authors.lastname: Gardyan
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Terranova
authors.forename: Joseph
authors.initials: J
authors.lastname: Barbosa
authors.forename: Jack
authors.initials: J
authors.lastname: Yan
authors.forename: Mark
authors.initials: M
authors.lastname: Bednarz
authors.forename: Suman
authors.initials: S
authors.lastname: Layek
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Courtney
authors.forename: Jerry
authors.initials: J
authors.lastname: Taylor
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Digeorge-Foushee
authors.forename: Suma
authors.initials: S
authors.lastname: Gopinathan
authors.forename: Debra
authors.initials: D
authors.lastname: Bruce
authors.forename: Traci
authors.initials: T
authors.lastname: Smith
authors.forename: Liam
authors.initials: L
authors.lastname: Moran
authors.forename: Emily
authors.initials: E
authors.lastname: O'Neill
authors.forename: Jeff
authors.initials: J
authors.lastname: Kramer
authors.forename: Zhong
authors.initials: Z
authors.lastname: Lai
authors.forename: S David
authors.initials: SD
authors.lastname: Kimball
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Liu
authors.forename: Weimei
authors.initials: W
authors.lastname: Sun
authors.forename: Sean
authors.initials: S
authors.lastname: Yu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Swaffield
authors.forename: Alan
authors.initials: A
authors.lastname: Wilson
authors.forename: Alan
authors.initials: A
authors.lastname: Main
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Carson
authors.forename: Tamas
authors.initials: T
authors.lastname: Oravecz
authors.forename: David J
authors.initials: DJ
authors.lastname: Augeri
mesh_terms: D000284:Administration, Oral; D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors*; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018655:Lymphocyte Count; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)