Tricyclic sulfones as potent, selective and efficacious RORγt inverse agonists - Exploring C6 and C8 SAR using late-stage functionalization

Bioorg Med Chem Lett. 2020 Dec 1;30(23):127521. doi: 10.1016/j.bmcl.2020.127521. Epub 2020 Aug 31.

Abstract

In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.

Keywords: Acanthosis; Inverse agonist; Late-stage functionalization; RORγt.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Drug Inverse Agonism
  • Female
  • Heterocyclic Compounds, 3-Ring / chemical synthesis
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics
  • Heterocyclic Compounds, 3-Ring / therapeutic use*
  • Interleukin-18
  • Male
  • Melanosis / chemically induced
  • Melanosis / drug therapy*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Molecular Structure
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Protein Binding
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis
  • Sulfones / pharmacokinetics
  • Sulfones / therapeutic use*

Substances

  • Heterocyclic Compounds, 3-Ring
  • Interleukin-18
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Sulfones