Altered activity profile of a tertiary silanol analog of multi-targeting nuclear receptor modulator T0901317

Bioorg Med Chem Lett. 2016 Apr 1;26(7):1817-20. doi: 10.1016/j.bmcl.2016.02.031. Epub 2016 Feb 12.

Abstract

We report the design, synthesis, and physicochemical/biological evaluation of novel silanol derivative 6 (sila-T) as a silanol analog of multi-target nuclear receptor modulator T0901317 (5). Compound 6 showed intermediate hydrophobicity between the corresponding alcohol 13 and perfluoroalcohol 5. While 5 exhibited potent activities toward liver X receptor α and β, farnesoid X receptor, pregnane X receptor (PXR) and retinoic acid receptor-related orphan receptor (ROR)γ, silanol 6 exhibited activity only toward PXR and RORs. Incorporation of silanol instead of perfluoroalcohol is a promising option for developing novel target-selective, biologically active compounds.

Keywords: Nuclear receptor; Pregnane X receptor (PXR); Retinoic acid receptor-related orphan receptor (ROR); Sila-substitution; Silanol; T0901317.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Hydrocarbons, Fluorinated / chemistry*
  • Hydrocarbons, Fluorinated / pharmacology*
  • Liver X Receptors
  • Models, Molecular
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
  • Orphan Nuclear Receptors / metabolism*
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / metabolism*
  • Silanes / chemistry*
  • Silanes / pharmacology*
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*

Substances

  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Orphan Nuclear Receptors
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Silanes
  • Sulfonamides
  • T0901317
  • silanol
  • farnesoid X-activated receptor