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Srikanth Venkatraman,
Francisco Velazquez,
Stephen Gavalas,
Wanli Wu,
Kevin X Chen,
Nair Anilkumar,
Frank Bennett,
Yuhua Huang,
Patrick Pinto,
Yueheng Jiang, [......],
Jose Duca,
Hsueh-Cheng Huang,
Sony Agrawal, Chuan-Kui Jiang,
Eric Ferrari,
Cheng Li,
Joseph Kozlowski,
Stuart Rosenblum,
Neng-Yang Shih,
F George Njoroge
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ABSTRACT: The characterization of HCV genome has identified various vital functional proteins involved in the life cycle of hepatitis C virus. This has resulted in many novel enzymatic targets that are potential for development of therapeutic agents. The HCV RNA dependent RNA polymerase (HCV NS5B) is one such essential enzyme for HCV replication that has been well characterized and studied by various groups to develop novel therapies for hepatitis C. In this paper, we describe our efforts towards the identification and structure-activity relationship (SAR) of novel tricyclic indole derivatives that bind close to the palm site of the NS5B polymerase. X-ray crystal structure of an inhibitor bound to the polymerase is also described.
Bioorganic & medicinal chemistry 01/2013; · 2.82 Impact Factor
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Gopinadhan N Anilkumar,
Oleg Selyutin,
Stuart B Rosenblum,
Qingbei Zeng,
Yueheng Jiang,
Tin-Yau Chan,
Haiyan Pu,
Li Wang,
Frank Bennett,
Kevin X Chen, [......],
Francisco Velazquez,
Srikanth Venkatraman,
Bancha Vibulbhan,
Sony Agrawal,
Eric Ferrari, Chuan-Kui Jiang,
H-C Huang,
Neng-Yang Shih,
F George Njoroge,
Joseph A Kozlowski
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ABSTRACT: Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053μM, replicon EC(50)=4.8μM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039μM, replicon EC(50)=0.011μM) with >100-fold improved replicon activity.
Bioorganic & medicinal chemistry letters 10/2011; 22(1):713-7. · 2.65 Impact Factor
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Gopinadhan N Anilkumar,
Charles A Lesburg,
Oleg Selyutin,
Stuart B Rosenblum,
Qingbei Zeng,
Yueheng Jiang,
Tin-Yau Chan,
Haiyan Pu,
Henry Vaccaro,
Li Wang, [......],
Boris Feld,
Eric Ferrari,
Zhiqing He, Chuan-Kui Jiang,
Robert E Palermo,
Patricia McMonagle,
H-C Huang,
Neng-Yang Shih,
George Njoroge,
Joseph A Kozlowski
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ABSTRACT: SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 μM, replicon EC(50)>100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and replicon activity.
Bioorganic & medicinal chemistry letters 09/2011; 21(18):5336-41. · 2.65 Impact Factor
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Cliff C. Cheng,
Xiaohua Huang,
Gerald W. Shipps,
Yu-Sen Wang,
Daniel F. Wyss,
Kyle A. Soucy, Chuan-kui Jiang,
Sony Agrawal,
Eric Ferrari,
Zhiqing He,
H.-C. Huang
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ABSTRACT: Pyridine carboxamide-based inhibitors of the hepatitis C virus (HCV) NS5B polymerase were diversified and optimized to a variety of topologically related scaffolds. In particular, the 2-methyl nicotinic acid scaffold was developed into inhibitors with improved biochemical (IC50-GT1b = 0.014 μM) and cell-based HCV replicon potency (EC50-GT1b = 0.7 μM). Biophysical and biochemical characterization identified this novel series of compounds as palm site binders to HCV polymerase.Keywords (keywords): Hepatitis C virus; HCV NS5B polymerase; palm site inhibitors; direct-acting antiviral (DAA); automated ligand identification system (ALIS); 2D 15N-HSQC
08/2010;
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Cliff C Cheng,
Gerald W Shipps,
Zhiwei Yang,
Noriyuki Kawahata,
Charles A Lesburg,
José S Duca,
Jamie Bandouveres,
Jack D Bracken, Chuan-kui Jiang,
Sony Agrawal,
Eric Ferrari,
H-C Huang
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ABSTRACT: SAR exploration from an initial hit, (S)-N-(2-cyclohexenylethyl)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)benzamide (1), identified using our proprietary automated ligand identification system (ALIS),(1) has led to a novel series of selective hepatitis C virus (HCV) NS5B polymerase inhibitors with improved in vitro potency as exemplified by (S)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)-N-isopentyl-N-methylbenzamidecarboxamide (41) (IC(50)=0.5 microM). The crystal structure of an analogue (44) was solved and provided rationalization of the SAR of this series, which binds in a distinct manner in the palm domain of NS5B, consistent with biochemical analysis using enzyme mutant variants. These data warrant further lead optimization efforts on this novel series of non-nucleoside inhibitors targeting the HCV polymerase.
Bioorganic & medicinal chemistry letters 02/2010; 20(7):2119-24. · 2.65 Impact Factor
