Benzofuran Derivatives as Potent, Orally Active S1P1 Receptor Agonists: A Preclinical Lead Molecule for MS

  • ACS Med Chem Lett. 2010 Nov 9;2(2):97-101. doi: 10.1021/ml100227q.
Ashis K Saha  1 ,  Xiang Yu  1 ,  Jian Lin  1 ,  Mercedes Lobera  1 ,  Anurag Sharadendu  1 ,  Srinivas Chereku  1 ,  Nili Schutz  1 ,  Dalia Segal  1 ,  Yael Marantz  1 ,  Dilara McCauley  1 ,  Scot Middleton  2 ,  Jerry Siu  2 ,  Roland W Bürli  3 ,  Janet Buys  4 ,  Michelle Horner  4 ,  Kevin Salyers  5 ,  Michael Schrag  5 ,  Hugo M Vargas  4 ,  Yang Xu  5 ,  Michele McElvain  6 ,  Han Xu  6
Affiliations
  • 1. EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
  • 2. Inflammation Research.
  • 3. Departments of Medicinal Chemistry.
  • 4. Comparative Biology and Safety Sciences.
  • 5. Pharmacokinetics and Drug Metabolism.
  • 6. Molecular Pharmacology.
PMID: 24900286 DOI: 10.1021/ml100227q
Abstract

We have discovered novel benzofuran-based S1P1 agonists with excellent in vitro potency and selectivity. 1-((4-(5-Benzylbenzofuran-2-yl)-3-fluorophenyl)methyl) azetidine-3-carboxylic acid (18) is a potent S1P1 agonist with >1000× selectivity over S1P3. It demonstrated a good in vitro ADME profile and excellent oral bioavailability across species. Dosed orally at 0.3 mg/kg, 18 significantly reduced blood lymphocyte counts 24 h postdose and demonstrated efficacy in a mouse EAE model of relapsing MS.

Keywords
S1P1; S1P3; Sphingosine-1 phosphate receptor; benzofuran; immunomodulators; lymphopenia; relapsing MS.