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

ABSTRACT: 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.

SUBMITTER: Lanman BA

PROVIDER: S-EPMC4018108 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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

Lanman Brian A BA Cee Victor J VJ Cheruku Srinivasa R SR Frohn Mike M Golden Jennifer J Lin Jian J Lobera Mercedes M Marantz Yael Y Muller Kristine M KM Neira Susana C SC Pickrell Alexander J AJ Rivenzon-Segal Dalia D Schutz Nili N Sharadendu Anurag A Yu Xiang X Zhang Zhaoda Z Buys Janet J Fiorino Mike M Gore Anu A Horner Michelle M Itano Andrea A McElvain Michele M Middleton Scot S Schrag Michael M Vargas Hugo M HM Xu Han H Xu Yang Y Zhang Xuxia X Siu Jerry J Bürli Roland W RW

ACS medicinal chemistry letters 20101109 2

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. ...[more]

PMID: 24900287

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