| Literature DB >> 24900263 |
Lewis D Pennington1, Kelvin K C Sham1, Alexander J Pickrell1, Paul E Harrington1, Michael J Frohn1, Brian A Lanman1, Anthony B Reed1, Michael D Croghan1, Matthew R Lee1, Han Xu1, Michele McElvain1, Yang Xu1, Xuxia Zhang1, Michael Fiorino1, Michelle Horner1, Henry G Morrison1, Heather A Arnett1, Christopher Fotsch1, Min Wong1, Victor J Cee1.
Abstract
The sphingosine-1-phosphate-1 receptor (S1P1) and its endogenous ligand sphingosine-1-phosphate (S1P) cooperatively regulate lymphocyte trafficking from the lymphatic system. Herein, we disclose 4-methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide (8), an uncommon example of a synthetic S1P1 agonist lacking a polar headgroup, which is shown to effect dramatic reduction of circulating lymphocytes (POC = -78%) in rat 24 h after a single oral dose (1 mg/kg). The excellent potency that 8 exhibits toward S1P1 (EC50 = 0.035 μM, 96% efficacy) and the >100-fold selectivity that it displays against receptor subtypes S1P2-5 suggest that it may serve as a valuable tool to understand the clinical relevance of selective S1P1 agonism.Entities:
Keywords: Sphingosine-1-phosphate-1 receptor agonist; immunosuppression; multiple sclerosis; peripheral lymphocyte count
Year: 2011 PMID： 24900263 PMCID： PMC4018088 DOI： 10.1021/ml2001399
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345