2. Academic Validation
  3. 4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P1

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

Affiliation

  • 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.

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