Imidazo[1,2-a]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization

  • ACS Med Chem Lett. 2012 May 24;3(7):565-9. doi: 10.1021/ml300090x.
J Brad Shotwell  1 ,  Subramanian Baskaran  1 ,  Pek Chong  1 ,  Katrina L Creech  2 ,  Renae M Crosby  1 ,  Hamilton Dickson  1 ,  Jing Fang  1 ,  Dulce Garrido  1 ,  Amanda Mathis  1 ,  Jack Maung  1 ,  Derek J Parks  2 ,  Jeffrey J Pouliot  1 ,  Daniel J Price  2 ,  Roopa Rai  1 ,  John W Seal 3rd  2 ,  Uli Schmitz  1 ,  Vincent W F Tai  1 ,  Michael Thomson  1 ,  Mi Xie  1 ,  Zhiping Z Xiong  1 ,  Andrew J Peat  1
Affiliations
  • 1. GlaxoSmithKline , Antiviral Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
  • 2. GlaxoSmithKline , Platform Technology and Science, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.
PMID: 24900511 DOI: 10.1021/ml300090x
Abstract

A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This series demonstrates potent in vitro inhibition of HCV replication (EC50 < 10 nM), direct binding to purified NS4B protein (IC50 < 20 nM), and an HCV resistance pattern associated with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV clinical assets, suggestive of the potential for additive or synergistic combination with other small molecule inhibitors of HCV replication.

Keywords
NS4B; hepatitis C virus; imidazo[1,2-a]pyridines; replicon.