Discovery and Structure-Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P1).
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P1 receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P1 agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P1 agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P3 are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
John L
JL
Gilmore
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
James E
JE
Sheppeck
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Scott H
SH
Watterson
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Lauren
L
Haque
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Parag
P
Mukhopadhyay
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Andrew J
AJ
Tebben
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Michael A
MA
Galella
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Ding Ren
DR
Shen
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Melissa
M
Yarde
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Mary Ellen
ME
Cvijic
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Virna
V
Borowski
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Kathleen
K
Gillooly
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Tracy
T
Taylor
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Kim W
KW
McIntyre
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Bethanne
B
Warrack
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Paul C
PC
Levesque
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Julia P
JP
Li
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Georgia
G
Cornelius
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Celia
C
D'Arienzo
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Anthony
A
Marino
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Praveen
P
Balimane
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Luisa
L
Salter-Cid
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Joel C
JC
Barrish
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
William J
WJ
Pitts
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Percy H
PH
Carter
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Jenny
J
Xie
Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
Alaric J
AJ
Dyckman
D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D004285:Dogs; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D019856:Ethanolamine / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D000882:Haplorhini; D006801:Humans; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D049349:Receptors, Lysosphingolipid; D019856:Ethanolamine