Synthesis of deuterium-labelled analogues of NLRP3 inflammasome inhibitor MCC950

Bioorg Med Chem Lett. 2018 Feb 15;28(4):793-795. doi: 10.1016/j.bmcl.2017.12.054. Epub 2017 Dec 26.

Abstract

This study describes the syntheses of di, tetra and hexa deuterated analogues of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950. In di and tetra deuterated analogues, deuteriums were incorporated into the 1,2,3,5,6,7-hexahydro-s-indacene moiety, whereas in the hexa deuterated MCC950 deuteriums were incorporated into the 2-(furan-3-yl)propan-2-ol moiety. The di deuterated MCC950 analogue was synthesised from 4-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one 5. Tetra deuterated analogues were synthesised in 10 chemical steps starting with 5-bromo-2,3-dihydro-1H-inden-1-one 9, whereas the hexa deuterated analogue was synthesised in four chemical steps starting with ethyl-3-furoate 24. All of the compounds exhibited similar activity to MCC950 (IC50 = 8 nM). These deuterated analogues are useful as internal standards in LC-MS analyses of biological samples from in vivo studies.

Keywords: Deuterium; Inflammasome; MCC950; NLRP3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatography, Liquid / methods
  • Deuterium
  • Furans
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacokinetics*
  • Humans
  • Indenes
  • Inflammasomes / antagonists & inhibitors*
  • Interleukin-1beta / metabolism
  • Macrophages / metabolism
  • Mass Spectrometry / methods
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • Reference Standards
  • Sulfonamides
  • Sulfones / chemical synthesis
  • Sulfones / chemistry
  • Sulfones / pharmacokinetics*

Substances

  • Furans
  • Heterocyclic Compounds, 4 or More Rings
  • Indenes
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Sulfonamides
  • Sulfones
  • N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide
  • Deuterium