4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P1

  • ACS Med Chem Lett. 2011 Jul 29;2(10):752-7. doi: 10.1021/ml2001399.
Lewis D Pennington  1 ,  Kelvin K C Sham  1 ,  Alexander J Pickrell  1 ,  Paul E Harrington  1 ,  Michael J Frohn  1 ,  Brian A Lanman  1 ,  Anthony B Reed  1 ,  Michael D Croghan  1 ,  Matthew R Lee  1 ,  Han Xu  1 ,  Michele McElvain  1 ,  Yang Xu  1 ,  Xuxia Zhang  1 ,  Michael Fiorino  1 ,  Michelle Horner  1 ,  Henry G Morrison  1 ,  Heather A Arnett  1 ,  Christopher Fotsch  1 ,  Min Wong  1 ,  Victor J Cee  1
Affiliations
  • 1. Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
PMID: 24900263 DOI: 10.1021/ml2001399
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.

Keywords
Sphingosine-1-phosphate-1 receptor agonist; immunosuppression; multiple sclerosis; peripheral lymphocyte count.