Isoform-selective thiazolo[5,4-b]pyridine S1P1 agonists possessing acyclic amino carboxylate head-groups

Bioorg Med Chem Lett. 2012 Feb 15;22(4):1779-83. doi: 10.1016/j.bmcl.2011.12.073. Epub 2011 Dec 21.

Abstract

Replacement of the azetidine carboxylate of an S1P(1) agonist development candidate, AMG 369, with a range of acyclic head-groups led to the identification of a novel, S1P(3)-sparing S1P(1) agonist, (-)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid (8c), which possessed good in vivo efficacy and pharmacokinetic properties. A 0.3mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24h post-dosing in female Lewis rats.

MeSH terms

  • Administration, Oral
  • Amines / chemistry*
  • Animals
  • Carboxylic Acids / chemistry*
  • Cyclization
  • Female
  • Inhibitory Concentration 50
  • Molecular Structure
  • Protein Binding / drug effects
  • Protein Isoforms / chemistry*
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Rats
  • Rats, Inbred Lew
  • Receptors, Lysosphingolipid / agonists*
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology

Substances

  • 2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo(5,4-b)pyridin-2-yl)phenyl)-2-methylbutanoic acid
  • Amines
  • Carboxylic Acids
  • Protein Isoforms
  • Pyridines
  • Receptors, Lysosphingolipid
  • Thiazoles
  • pyridine