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. 2012 May 24;3(7):565-9.
doi: 10.1021/ml300090x. eCollection 2012 Jul 12.

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

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

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

J Brad Shotwell et al. ACS Med Chem Lett. .

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.

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Figures

Figure 1
Figure 1
Tritiated NS4B probes and anguizole.
Figure 2
Figure 2
Equilibirum binding of 1d for isolated His-Tagged NS4B. Kd = 30 nM (see Supporting Information).
Figure 3
Figure 3
IC50 determination for 1b via 1d displacement from purified NS4B.
Scheme 1
Scheme 1. Synthesis of Core and Elaboration
Conditions: (i) α-bromopyruvate, DMF, 50 °C (83%); (ii) NCS, DMF, 50 °C, 1 h, (91%); (iii) 3-furanylboronic acid, K3PO4, MeCN, Pd(dppf)Cl2, (82%); (iv) amine, HATU, DIPEA, DMF (20–85%).−
See this image and copyright information in PMC

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