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

J Brad Shotwell; Subramanian Baskaran; Pek Chong; Katrina L Creech; Renae M Crosby; Hamilton Dickson; Jing Fang; Dulce Garrido; Amanda Mathis; Jack Maung; Derek J Parks; Jeffrey J Pouliot; Daniel J Price; Roopa Rai; John W Seal 3rd; Uli Schmitz; Vincent W F Tai; Michael Thomson; Mi Xie; Zhiping Z Xiong; Andrew J Peat

doi:10.1021/ml300090x

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. eCollection 2012 Jul 12.

Authors

J Brad Shotwell¹, Subramanian Baskaran¹, Pek Chong¹, Katrina L Creech², Renae M Crosby¹, Hamilton Dickson¹, Jing Fang¹, Dulce Garrido¹, Amanda Mathis¹, Jack Maung¹, Derek J Parks², Jeffrey J Pouliot¹, Daniel J Price², Roopa Rai¹, John W Seal 3rd², Uli Schmitz¹, Vincent W F Tai¹, Michael Thomson¹, Mi Xie¹, Zhiping Z Xiong¹, Andrew J Peat¹

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.

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.