Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A)

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2968-72. doi: 10.1016/j.bmcl.2012.02.041. Epub 2012 Feb 24.

Abstract

A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model.

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Guinea Pigs
  • Heterocyclic Compounds, 4 or More Rings / chemistry*
  • Heterocyclic Compounds, 4 or More Rings / metabolism
  • Inflammation / drug therapy
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Mice
  • Models, Molecular
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Protein Binding / drug effects
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Rats

Substances

  • GSK1210151A
  • Heterocyclic Compounds, 4 or More Rings
  • Isoxazoles
  • Nerve Tissue Proteins
  • Quinolines