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

被引:24
|
作者
Yan, Lin
Huo, Pei
Doherty, George
Toth, Lesile
Hale, Jeffrey J.
Mills, Sander G.
Hajdu, Richard
Keohane, Carol A.
Rosenbach, Mark J.
Milligan, James A.
Shei, Gan-Ju
Chrebet, Gary
Bergstrom, James
Card, Deborah
Quackenbush, Elizabeth
Wickham, Alexandra
Mandala, Suzanne M.
机构
[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA
[2] Merck Res Labs, Dept Immunol & Rheumatol, Rahway, NJ 07065 USA
[3] Merck Res Labs, Dept Pharmacol, Rahway, NJ 07065 USA
关键词
sphingosine-1-phosphate (S1P) receptors; agonists; lymphocyte lowering; immunosuppression; transplantation; 3-arylpropionic acids;
D O I
10.1016/j.bmcl.2006.04.084
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 3-arylpropionic acids were synthesized as S1P(1) receptor agonists. Structure-activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P(1) binding against S1P(2-5). These highly selective SIP, 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 S1P(1) agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3679 / 3683
页数:5
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