Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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.

PubMed Disclaimer

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

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kim A.; Timm J. Resistance mechanisms in HCV: from evolution to intervention. Expert Rev. Anti-Infect. Ther. 2008, 64463–478. - PubMed
    1. Almasio P.; Ingrassia D.; Vergara B.; Filosto S. New therapeutic prospects in HCV treatment. Expert Rev. Anti-Infect. Ther. 2008, 66775–779. - PubMed
    1. Kwong A.; Kauffman R.; Hurter P.; Mueller P. Discovery and development of telaprevir: an NS3–4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat. Biotechnol. 2011, 2911993–1003. - PubMed
    1. Chen K.; Njoroge F. The Journey to the Discovery of Boceprevir: An NS3-NS4 HCV Protease Inhibitor for the Treatment of Chronic Hepatitis C. Prog. Med. Chem. 2010, 49, 1–36. - PubMed
    1. Soriano V.; Vispo E.; Poveda E.; Labarga P.; Martin-Carbonero L.; Fernandez-Montero J.; Barreiro P. Directly acting antivirals against hepatitis C virus. J. Antimicrob. Chemother. 2011, 6681673–86. - PubMed