1,5-Benzodiazepine inhibitors of HCV NS5B polymerase.

David Mcgowan; Origene Nyanguile; Maxwell D Cummings; Sandrine Vendeville; Koen Vandyck; Walter Van Den Broeck; Carlo W. Boutton; Hendrik De Bondt; Ludo Quirynen; Katie Amssoms; Jean-Francois Bonfati; Stefaan Last; Klara Rombauts; Abdellah Tahri; Lili Hu; Frederic Delouvroy; K. Vermeiren; Genevieve Vandercruyssen; Liesbet Van Der Helm; Erna Cleiren; Wendy Mostmans; Pedro Lory; Geert Pille; Kristof Van Emelen; Gregory Fanning; Frederik Pauwels; Tse-I Lin; Kenneth Simmen; Pierre Raboisson

1,5-Benzodiazepine inhibitors of HCV NS5B polymerase.

David Mcgowan, Origene Nyanguile, Maxwell D Cummings, Sandrine Vendeville, Koen Vandyck, Walter Van Den Broeck, Carlo W. Boutton, Hendrik De Bondt, Ludo Quirynen, Katie Amssoms, Jean-Francois Bonfati, Stefaan Last, Klara Rombauts, Abdellah Tahri, Lili Hu, Frederic Delouvroy, K. Vermeiren, Genevieve Vandercruyssen, Liesbet Van Der Helm, Erna CleirenWendy Mostmans, Pedro Lory, Geert Pille, Kristof Van Emelen, Gregory Fanning, Frederik Pauwels, Tse-I Lin, Kenneth Simmen, Pierre Raboisson

Analytical Chemistry and Pharmaceutical Technology

Research output: Contribution to journal › Article › peer-review

62 Citations (Scopus)

Abstract

Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent ( replicon EC(50) = 400 nM and 270 nM, respectively) and selective (CC(50) > 20 mu M) inhibitors of HCV replication. These data warrant further lead-optimization efforts.

Original language	English
Pages (from-to)	2492-2496
Number of pages	5
Journal	Bioorg Med Chem Lett
Volume	19
Issue number	May
Publication status	Published - 2009

Keywords

Hepatitis C virus
HCV
Polymerase
Benzodiazepine
Hepatitis-C

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http://www.ncbi.nlm.nih.gov/pubmed/19342234

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Mcgowan, D., Nyanguile, O., Cummings, M. D., Vendeville, S., Vandyck, K., Van Den Broeck, W., Boutton, C. W., De Bondt, H., Quirynen, L., Amssoms, K., Bonfati, J-F., Last, S., Rombauts, K., Tahri, A., Hu, L., Delouvroy, F., Vermeiren, K., Vandercruyssen, G., Van Der Helm, L., ... Raboisson, P. (2009). 1,5-Benzodiazepine inhibitors of HCV NS5B polymerase. Bioorg Med Chem Lett, 19(May), 2492-2496. http://www.ncbi.nlm.nih.gov/pubmed/19342234

Mcgowan, David ; Nyanguile, Origene ; Cummings, Maxwell D ; Vendeville, Sandrine ; Vandyck, Koen ; Van Den Broeck, Walter ; Boutton, Carlo W. ; De Bondt, Hendrik ; Quirynen, Ludo ; Amssoms, Katie ; Bonfati, Jean-Francois ; Last, Stefaan ; Rombauts, Klara ; Tahri, Abdellah ; Hu, Lili ; Delouvroy, Frederic ; Vermeiren, K. ; Vandercruyssen, Genevieve ; Van Der Helm, Liesbet ; Cleiren, Erna ; Mostmans, Wendy ; Lory, Pedro ; Pille, Geert ; Van Emelen, Kristof ; Fanning, Gregory ; Pauwels, Frederik ; Lin, Tse-I ; Simmen, Kenneth ; Raboisson, Pierre. / 1,5-Benzodiazepine inhibitors of HCV NS5B polymerase. In: Bioorg Med Chem Lett. 2009 ; Vol. 19, No. May. pp. 2492-2496.

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title = "1,5-Benzodiazepine inhibitors of HCV NS5B polymerase.",

abstract = "Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent ( replicon EC(50) = 400 nM and 270 nM, respectively) and selective (CC(50) > 20 mu M) inhibitors of HCV replication. These data warrant further lead-optimization efforts.",

keywords = "Hepatitis C virus, HCV, Polymerase, Benzodiazepine, Hepatitis-C",

author = "David Mcgowan and Origene Nyanguile and Cummings, {Maxwell D} and Sandrine Vendeville and Koen Vandyck and {Van Den Broeck}, Walter and Boutton, {Carlo W.} and {De Bondt}, Hendrik and Ludo Quirynen and Katie Amssoms and Jean-Francois Bonfati and Stefaan Last and Klara Rombauts and Abdellah Tahri and Lili Hu and Frederic Delouvroy and K. Vermeiren and Genevieve Vandercruyssen and {Van Der Helm}, Liesbet and Erna Cleiren and Wendy Mostmans and Pedro Lory and Geert Pille and {Van Emelen}, Kristof and Gregory Fanning and Frederik Pauwels and Tse-I Lin and Kenneth Simmen and Pierre Raboisson",

year = "2009",

language = "English",

volume = "19",

pages = "2492--2496",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "May",

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Mcgowan, D, Nyanguile, O, Cummings, MD, Vendeville, S, Vandyck, K, Van Den Broeck, W, Boutton, CW, De Bondt, H, Quirynen, L, Amssoms, K, Bonfati, J-F, Last, S, Rombauts, K, Tahri, A, Hu, L, Delouvroy, F, Vermeiren, K, Vandercruyssen, G, Van Der Helm, L, Cleiren, E, Mostmans, W, Lory, P, Pille, G, Van Emelen, K, Fanning, G, Pauwels, F, Lin, T-I, Simmen, K & Raboisson, P 2009, '1,5-Benzodiazepine inhibitors of HCV NS5B polymerase.', Bioorg Med Chem Lett, vol. 19, no. May, pp. 2492-2496. <http://www.ncbi.nlm.nih.gov/pubmed/19342234>

1,5-Benzodiazepine inhibitors of HCV NS5B polymerase. / Mcgowan, David; Nyanguile, Origene; Cummings, Maxwell D; Vendeville, Sandrine; Vandyck, Koen; Van Den Broeck, Walter; Boutton, Carlo W.; De Bondt, Hendrik; Quirynen, Ludo; Amssoms, Katie; Bonfati, Jean-Francois; Last, Stefaan; Rombauts, Klara; Tahri, Abdellah; Hu, Lili; Delouvroy, Frederic; Vermeiren, K.; Vandercruyssen, Genevieve; Van Der Helm, Liesbet; Cleiren, Erna; Mostmans, Wendy; Lory, Pedro; Pille, Geert; Van Emelen, Kristof; Fanning, Gregory; Pauwels, Frederik; Lin, Tse-I; Simmen, Kenneth; Raboisson, Pierre.

In: Bioorg Med Chem Lett, Vol. 19, No. May, 2009, p. 2492-2496.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 1,5-Benzodiazepine inhibitors of HCV NS5B polymerase.

AU - Mcgowan, David

AU - Nyanguile, Origene

AU - Cummings, Maxwell D

AU - Vendeville, Sandrine

AU - Vandyck, Koen

AU - Van Den Broeck, Walter

AU - Boutton, Carlo W.

AU - De Bondt, Hendrik

AU - Quirynen, Ludo

AU - Amssoms, Katie

AU - Bonfati, Jean-Francois

AU - Last, Stefaan

AU - Rombauts, Klara

AU - Tahri, Abdellah

AU - Hu, Lili

AU - Delouvroy, Frederic

AU - Vermeiren, K.

AU - Vandercruyssen, Genevieve

AU - Van Der Helm, Liesbet

AU - Cleiren, Erna

AU - Mostmans, Wendy

AU - Lory, Pedro

AU - Pille, Geert

AU - Van Emelen, Kristof

AU - Fanning, Gregory

AU - Pauwels, Frederik

AU - Lin, Tse-I

AU - Simmen, Kenneth

AU - Raboisson, Pierre

PY - 2009

Y1 - 2009

N2 - Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent ( replicon EC(50) = 400 nM and 270 nM, respectively) and selective (CC(50) > 20 mu M) inhibitors of HCV replication. These data warrant further lead-optimization efforts.

AB - Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent ( replicon EC(50) = 400 nM and 270 nM, respectively) and selective (CC(50) > 20 mu M) inhibitors of HCV replication. These data warrant further lead-optimization efforts.

KW - Hepatitis C virus

KW - HCV

KW - Polymerase

KW - Benzodiazepine

KW - Hepatitis-C

M3 - Article

VL - 19

SP - 2492

EP - 2496

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

SN - 0960-894X

IS - May

ER -

1,5-Benzodiazepine inhibitors of HCV NS5B polymerase.

Abstract

Keywords

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