Discovery of potent 3,5-diphenyl-1,2,4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3.
A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.
Li
Zhen
Z
Department of Medicinal Chemistry, Merck Research Laboratory, Rahway, New Jersey 07065, USA. zhen_li@merck.com
Chen
Weirong
W
Hale
Jeffrey J
JJ
Lynch
Christopher L
CL
Mills
Sander G
SG
Hajdu
Richard
R
Keohane
Carol Ann
CA
Rosenbach
Mark J
MJ
Milligan
James A
JA
Shei
Gan-Ju
GJ
Chrebet
Gary
G
Parent
Stephen A
SA
Bergstrom
James
J
Card
Deborah
D
Forrest
Michael
M
Quackenbush
Elizabeth J
EJ
Wickham
L Alexandra
LA
Vargas
Hugo
H
Evans
Rose M
RM
Rosen
Hugh
H
Mandala
Suzanne
S
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018655:Lymphocyte Count; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D016038:Skin Transplantation; D013329:Structure-Activity Relationship
D007166:Immunosuppressive Agents; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid