Discovery of a novel class of zwitterionic, potent, selective and orally active S1P₁ direct agonists

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7672-6. doi: 10.1016/j.bmcl.2012.09.110. Epub 2012 Oct 11.

Abstract

Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural-activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models.

MeSH terms

  • Administration, Oral
  • Animals
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Lymphopenia / blood
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Receptors, Lysosphingolipid / agonists*
  • Sphingosine-1-Phosphate Receptors
  • Structure-Activity Relationship
  • Thiadiazoles / administration & dosage
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / pharmacology*

Substances

  • Receptors, Lysosphingolipid
  • S1PR1 protein, rat
  • Sphingosine-1-Phosphate Receptors
  • Thiadiazoles
  • 1,3,4-thiadiazole