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.
Jonathan Seal  1 ,  Yann Lamotte ,  Frédéric Donche ,  Anne Bouillot ,  Olivier Mirguet ,  Françoise Gellibert ,  Edwige Nicodeme ,  Gael Krysa ,  Jorge Kirilovsky ,  Soren Beinke ,  Scott McCleary ,  Inma Rioja ,  Paul Bamborough ,  Chun-Wa Chung ,  Laurie Gordon ,  Toni Lewis ,  Ann L Walker ,  Leanne Cutler ,  David Lugo ,  David M Wilson ,  Jason Witherington ,  Kevin Lee ,  Rab K Prinjha
Affiliations
  • 1. Epinova DPU, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage, Hertfordshire, UK. [email protected]
PMID: 22437115 DOI: 10.1016/j.bmcl.2012.02.041
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.

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