Discovery of 3-arylpropionic acids as potent agonists of sphingosine-1-phosphate receptor-1 (S1P1) with high selectivity against all other known S1P receptor subtypes.
A series of 3-arylpropionic acids were synthesized as S1P1 receptor agonists. Structure-activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P1 binding against S1P2-5. These highly selective S1P1 agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin transplantation model, supporting that S1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models.
Yan
Lin
L
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. lin_yan@merck.com
Huo
Pei
P
Doherty
George
G
Toth
Lesile
L
Hale
Jeffrey J
JJ
Mills
Sander G
SG
Hajdu
Richard
R
Keohane
Carol A
CA
Rosenbach
Mark J
MJ
Milligan
James A
JA
Shei
Gan-Ju
GJ
Chrebet
Gary
G
Bergstrom
James
J
Card
Deborah
D
Quackenbush
Elizabeth
E
Wickham
Alexandra
A
Mandala
Suzanne M
SM
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008024:Ligands; D018655:Lymphocyte Count / Q000662:veterinary; D051379:Mice; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D016038:Skin Transplantation; D013329:Structure-Activity Relationship
D007166:Immunosuppressive Agents; D008024:Ligands; D010666:Phenylpropionates; D049349:Receptors, Lysosphingolipid