Highly selective and potent agonists of sphingosine-1-phosphate 1 (S1P1) receptor.
Novel series of sphingosine-1-phosphate (S1P) receptor agonists were developed through a systematic SAR aimed to achieve high selectivity for a single member of the S1P family of receptors, S1P1. The optimized structure represents a highly S1P1-selective and efficacious agonist: S1P1/S1P2, S1P1/S1P3, S1P1/S1P4>10,000-fold, S1P1/S1P5>600-fold, while EC50 (S1P1) <0.2 nM. In vivo experiments are consistent with S1P1 receptor agonism alone being sufficient for achieving desired lymphocyte-lowering effect.
Vachal
Petr
P
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. petr_vachal@merck.com
Toth
Leslie M
LM
Hale
Jeffrey J
JJ
Yan
Lin
L
Mills
Sander G
SG
Chrebet
Gary L
GL
Koehane
Carol A
CA
Hajdu
Richard
R
Milligan
James A
JA
Rosenbach
Mark J
MJ
Mandala
Suzanne
S