2. Academic Validation
  3. Benzofuran Derivatives as Potent, Orally Active S1P1 Receptor Agonists: A Preclinical Lead Molecule for MS

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

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.

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