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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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Kevin X Chen,
Charles A Lesburg,
Bancha Vibulbhan,
Weiying Yang,
Tin-Yau Chan,
Srikanth Venkatraman,
Francisco Velazquez,
Qingbei Zeng,
Frank Bennett,
Gopinadhan N Anilkumar, [......],
Haiyan Pu,
Sony Agrawal,
Boris Feld,
Hsueh-Cheng Huang,
Cheng Li,
Kuo-Chi Cheng,
Neng-Yang Shih,
Joseph A Kozlowski,
Stuart B Rosenblum,
F George Njoroge
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ABSTRACT: Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 μM·h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.
Journal of Medicinal Chemistry 03/2012; 55(5):2089-101. · 4.80 Impact Factor
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Kevin X Chen,
Bancha Vibulbhan,
Weiying Yang,
Mousumi Sannigrahi,
Francisco Velazquez,
Tin-Yau Chan,
Srikanth Venkatraman,
Gopinadhan N Anilkumar,
Qingbei Zeng,
Frank Bennet, [......],
Oleg Selyutin,
Sony Agrawal,
Boris Feld,
Hsueh-Cheng Huang,
Cheng Li,
Kuo-Chi Cheng,
Neng-Yang Shih,
Joseph A Kozlowski,
Stuart B Rosenblum,
F George Njoroge
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ABSTRACT: Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 μM) and cell-based replicon (EC(50) = 0.02 μM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 μM·h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.
Journal of Medicinal Chemistry 12/2011; 55(2):754-65. · 4.80 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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ABSTRACT: The HIV-1 CCR5 co-receptor is a member of the chemokine receptor family of G-protein coupled receptors; for which a number of small molecule antagonists, such as vicriviroc (VCV), have been developed to inhibit HIV-1 R5-tropic replication. In this study, we analyzed an HIV-1 subtype D envelope gene from a clinical trial subject who developed complete resistance to VCV. The HIV-1 resistant envelope has six predominant amino acid changes in the V3 loop, together with one change in the C4 domain of gp120, which are fully responsible for the resistance phenotype. V3 loop mutations Q315E and R321G are essential for resistance to VCV, whereas E328K and G429R in C4 contribute significantly to the infectivity of the resistant variant. Collectively, these amino acid changes influenced the interaction of gp120 with both the N-terminus and ECL2 region of CCR5.
Virology 02/2010; 400(1):145-55. · 3.35 Impact Factor
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ABSTRACT: Vicriviroc (VCV) is a small-molecule CCR5 coreceptor antagonist currently in clinical trials for treatment of R5-tropic human immunodeficiency virus type 1 (HIV-1) infection. With this drug in development, identification of resistance mechanisms to VCV is needed to allow optimal outcomes in clinical practice. In this study we further characterized VCV resistance in a lab-adapted, VCV-resistant RU570 virus (RU570-VCV(res)). We show that K305R, R315Q, and K319T amino acid changes in the V3 loop, along with P437S in C4, completely reproduced the resistance phenotype in a chimeric ADA envelope containing the C2-V5 region from RU570 passage control gp120. The K305R amino acid change primarily impacted the degree of resistance, whereas K319T contributed to both resistance and virus infectivity. The P437S mutation in C4 had more influence on the relative degree of virus infectivity, while the R315Q mutation contributed to the virus concentration-dependent phenotypic resistance pattern observed for RU570-VCV(res). RU570-VCV(res) pseudovirus entry with VCV-bound CCR5 was dramatically reduced by Y10A, D11A, Y14A, and Y15A mutations in the N terminus of CCR5, whereas these mutations had less impact on entry in the absence of VCV. Notably, an additional Q315E/I317F substitution in the crown region of the V3 loop enhanced resistance to VCV, resulting in a stronger dependence on the N terminus for viral entry. By fitting the envelope mutations to a molecular model of a recently described docked N-terminal CCR5 peptide consisting of residues 2 to 15 in complex with HIV-1 gp120 CD4, potential new interactions in gp120 with the N terminus of CCR5 were uncovered. The cumulative results of this study suggest that as the RU570 VCV-resistant virus adapted to use the drug-bound receptor, it also developed an increased reliance on the N terminus of CCR5.
Journal of Virology 09/2009; 83(23):12151-63. · 5.40 Impact Factor
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ABSTRACT: A series of 4H-pyrazolo[1,5-a]pyrimidin-7-one derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase. A number of these compounds exhibited potent activity in enzymatic assay. The synthesis and structure-activity relationship are also described.
Bioorganic & medicinal chemistry letters 09/2009; 19(18):5363-7. · 2.65 Impact Factor
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Michael P Dwyer,
Kamil Paruch,
Carmen Alvarez,
Ronald J Doll,
Kerry Keertikar, Jose Duca,
Thierry O Fischmann,
Alan Hruza,
Vincent Madison,
Emma Lees,
David Parry,
Wolfgang Seghezzi,
Nicole Sgambellone,
Frances Shanahan,
Derek Wiswell,
Timothy J Guzi
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ABSTRACT: A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) inhibitors. From the in-vitro and cell-based analysis, the pyrazolo[1,5-a]pyrimidine core (represented by 9) emerged as the superior core for further elaboration in the identification of novel CDK2 inhibitors.
Bioorganic & Medicinal Chemistry Letters 12/2007; 17(22):6216-9. · 2.55 Impact Factor
