Potent S1P receptor agonists replicate the pharmacologic actions of the novel immune modulator FTY720.
Alteration in lymphocyte trafficking and prevention of graft rejection in rodents observed on exposure to FTY720 (1) or its corresponding phosphate ester 2 can be induced by the systemic administration of potent sphingosine-1-phosphate receptor agonists exemplified by 19. The similar S1P receptor profiles of 2 and 19 coupled with their comparable potency in vivo supports a connection between S1P receptor agonism and immunosuppressive efficacy.
Hale
Jeffrey J
JJ
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. jeffrey_hale@merck.com
Neway
William
W
Mills
Sander G
SG
Hajdu
Richard
R
Ann Keohane
Carol
C
Rosenbach
Mark
M
Milligan
James
J
Shei
Gan-Ju
GJ
Chrebet
Gary
G
Bergstrom
James
J
Card
Deborah
D
Koo
Gloria C
GC
Koprak
Sam L
SL
Jackson
Jesse J
JJ
Rosen
Hugh
H
Mandala
Suzanne
S
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D011409:Propylene Glycols / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives
D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine