Novel 5- and 6-subtituted benzothiazoles with improved physicochemical properties: potent S1P₁ agonists with in vivo lymphocyte-depleting activity

Bioorg Med Chem Lett. 2012 Jan 1;22(1):628-33. doi: 10.1016/j.bmcl.2011.10.069. Epub 2011 Oct 28.

Abstract

An SAR campaign designed to increase polarity in the 'tail' region of benzothiazole 1 resulted in two series of structurally novel 5-and 6-substituted S1P(1) agonists. Structural optimization for potency ultimately delivered carboxamide (+)-11f, which in addition to possessing improved physicochemical properties relative to starting benzothiazole 1, also displayed good S1P(3) selectivity and acceptable in vivo lymphocyte-depleting activity.

MeSH terms

  • Animals
  • Benzothiazoles / chemistry*
  • CHO Cells
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical / methods
  • Chemistry, Physical / methods
  • Cricetinae
  • Cricetulus
  • Drug Design
  • Female
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Ketones
  • Lymphocytes / cytology
  • Lymphocytes / drug effects*
  • Models, Chemical
  • Rats
  • Rats, Inbred Lew
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Lysosphingolipid / agonists*
  • Receptors, Lysosphingolipid / chemistry*

Substances

  • Benzothiazoles
  • Ketones
  • Receptors, G-Protein-Coupled
  • Receptors, Lysosphingolipid
  • Green Fluorescent Proteins