2. Academic Validation
  3. 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)

  • ACS Med Chem Lett. 2010 Nov 9;2(2):102-6. doi: 10.1021/ml100228m.
Brian A Lanman 1,  Victor J Cee 1,  Srinivasa R Cheruku 2,  Mike Frohn 1,  Jennifer Golden 1,  Jian Lin 2,  Mercedes Lobera 2,  Yael Marantz 2,  Kristine M Muller 1,  Susana C Neira 1,  Alexander J Pickrell 1,  Dalia Rivenzon-Segal 2,  Nili Schutz 2,  Anurag Sharadendu 2,  Xiang Yu 2,  Zhaoda Zhang 2,  Janet Buys 1,  Mike Fiorino 1,  Anu Gore 1,  Michelle Horner 1,  Andrea Itano 1,  Michele McElvain 1,  Scot Middleton 1,  Michael Schrag 1,  Hugo M Vargas 1,  Han Xu 1,  Yang Xu 1,  Xuxia Zhang 1,  Jerry Siu 1,  Roland W Bürli 1
Affiliations

Affiliations

  • 1 Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
  • 2 EPIX Pharmaceuticals Inc., 167 Worcester Street, Suite 201, Wellesley Hills, Massachusetts 02481, United States.
PMID: 24900287 DOI: 10.1021/ml100228m
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.

Keywords

S1P1; Sphingosine-1-phosphate receptor; agonist; inflammation; lymphocyte.

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