Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders.
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.
Bagdanoff
Jeffrey T
JT
Lexicon Pharmaceuticals, Princeton, New Jersey, USA. jbagdanoff@lexpharma.com
Donoviel
Michael S
MS
Nouraldeen
Amr
A
Tarver
James
J
Fu
Qinghong
Q
Carlsen
Marianne
M
Jessop
Theodore C
TC
Zhang
Haiming
H
Hazelwood
Jill
J
Nguyen
Huy
H
Baugh
Simon D P
SD
Gardyan
Michael
M
Terranova
Kristen M
KM
Barbosa
Joseph
J
Yan
Jack
J
Bednarz
Mark
M
Layek
Suman
S
Courtney
Lawrence F
LF
Taylor
Jerry
J
Digeorge-Foushee
Ann Marie
AM
Gopinathan
Suma
S
Bruce
Debra
D
Smith
Traci
T
Moran
Liam
L
O'Neill
Emily
E
Kramer
Jeff
J
Lai
Zhong
Z
Kimball
S David
SD
Liu
Qingyun
Q
Sun
Weimei
W
Yu
Sean
S
Swaffield
Jonathan
J
Wilson
Alan
A
Main
Alan
A
Carson
Kenneth G
KG
Oravecz
Tamas
T
Augeri
David J
DJ
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
D004791:Enzyme Inhibitors; D007093:Imidazoles; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)