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
  • 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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