Discovery and optimization of new oxadiazole substituted thiazole RORγt inverse agonists through a bioisosteric amide replacement approach

Bioorg Med Chem Lett. 2020 Jun 15;30(12):127174. doi: 10.1016/j.bmcl.2020.127174. Epub 2020 Apr 7.

Abstract

Starting from previously identified thiazole-2-carboxamides exemplified by compound 1/6, two new series of RORγt inverse agonists with significantly improved aqueous solubility, ADME parameters and oral PK properties were discovered. These scaffolds were identified from a bioisosteric amide replacement approach. Amongst the variety of heterocycles explored, a 1,3,4-oxadiazole led to compounds with the best overall profile for SAR development and in vivo exploration. In an ex vivo mouse PD model, concentration dependent efficacy was demonstrated and compounds 3/5 and 6/3 were profiled in a 5-day rat tolerability study.

Keywords: Autoimmune diseases; Bioisostere; Nuclear receptor; Oxadiazole; RORc; RORγt.

MeSH terms

  • Administration, Oral
  • Amides / administration & dosage
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Oxadiazoles / administration & dosage
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Thiazoles / administration & dosage
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • Amides
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Oxadiazoles
  • Thiazoles