4-Methoxy- N -[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P 1
Year: 2011
Type: article
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.
Source: ACS Medicinal Chemistry Letters
DOI: 10.1021/ml2001399
Authors: Lewis D. Pennington, Kelvin K. C. Sham, Alexander J. Pickrell, Paul E. Harrington, Michael J. Frohn, Brian A. Lanman, Anthony B. Reed, Michael D. Croghan, Matthew R. Lee, Han Xu, Michele McElvain, Yang Xu, Xuxia Zhang, Michael Fiorino, Michelle Horner, Henry G. Morrison, Heather A. Arnett, Christopher Fotsch, Min Wong, Victor J. Cee
Institution: Amgen (United States)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2039734357