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

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.

SUBMITTER: Saha AK

PROVIDER: S-EPMC4017978 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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

Saha Ashis K AK Yu Xiang X Lin Jian J Lobera Mercedes M Sharadendu Anurag A Chereku Srinivas S Schutz Nili N Segal Dalia D Marantz Yael Y McCauley Dilara D Middleton Scot S Siu Jerry J Bürli Roland W RW Buys Janet J Horner Michelle M Salyers Kevin K Schrag Michael M Vargas Hugo M HM Xu Yang Y McElvain Michele M Xu Han H

ACS medicinal chemistry letters 20101109 2

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 M ...[more]

PMID: 24900286

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