Discovery of a Potent, S1P3-Sparing Benzothiazole Agonist of Sphingosine-1-Phosphate Receptor 1 (S1P1)

Discovery of a Potent, S1P3-Sparing Benzothiazole Agonist of Sphingosine-1-Phosphate Receptor 1 (S1P1)

Optimization of a benzofuranyl S1P1 agonist lead compound (3) led to the discovery of 1-(3-fluoro-4-(5-(2-fluorobenzyl)benzo[d]thiazol-2-yl)benzyl)azetidine-3-carboxylic acid (14), a potent S1P1 agonist with minimal activity at S1P3. Dosed orally at 0.3 mg/kg, 14 significantly reduced blood lymphocy...

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Veröffentlicht in:ACS medicinal chemistry letters 2011-02, Vol.2 (2), p.102-106
Hauptverfasser: Lanman, Brian A, Cee, Victor J, Cheruku, Srinivasa R, Frohn, Mike, Golden, Jennifer, Lin, Jian, Lobera, Mercedes, Marantz, Yael, Muller, Kristine M, Neira, Susana C, Pickrell, Alexander J, Rivenzon-Segal, Dalia, Schutz, Nili, Sharadendu, Anurag, Yu, Xiang, Zhang, Zhaoda, Buys, Janet, Fiorino, Mike, Gore, Anu, Horner, Michelle, Itano, Andrea, McElvain, Michele, Middleton, Scot, Schrag, Michael, Vargas, Hugo M, Xu, Han, Xu, Yang, Zhang, Xuxia, Siu, Jerry, Bürli, Roland W
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Sprache:eng
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Zusammenfassung:Optimization of a benzofuranyl S1P1 agonist lead compound (3) led to the discovery of 1-(3-fluoro-4-(5-(2-fluorobenzyl)benzo[d]thiazol-2-yl)benzyl)azetidine-3-carboxylic acid (14), a potent S1P1 agonist with minimal activity at S1P3. Dosed orally at 0.3 mg/kg, 14 significantly reduced blood lymphocyte counts 24 h postdose and attenuated a delayed type hypersensitivity (DTH) response to antigen challenge.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml100228m