Advanced search
1 file | 1.16 MB

Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (MK-3281), a potent and orally bioavailable finger-loop inhibitor of the hepatitis C virus NS5B polymerase

(2011) JOURNAL OF MEDICINAL CHEMISTRY. 54(1). p.289-301
Author
Organization
Abstract
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain Structure activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.
Keywords
DEPENDENT RNA-POLYMERASE, CHIMERIC HUMAN LIVERS, DE-NOVO INITIATION, UPA-SCID MOUSE, ALLOSTERIC INHIBITORS, NONNUCLEOSIDE INHIBITORS, HCVNS5B POLYMERASE, IN-VIVO, BENZIMIDAZOLE DERIVATIVES, ANTIVIRAL ACTIVITY

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 1.16 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Narjes, Frank, Benedetta Crescenzi, Marco Ferrara, Jörg Habermann, Stefania Colarusso, Maria del Rosario Ferreira, Ian Stansfield, et al. 2011. “Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-loop Inhibitor of the Hepatitis C Virus NS5B Polymerase.” Journal of Medicinal Chemistry 54 (1): 289–301.
APA
Narjes, F., Crescenzi, B., Ferrara, M., Habermann, J., Colarusso, S., Ferreira, M. del R., Stansfield, I., et al. (2011). Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (MK-3281), a potent and orally bioavailable finger-loop inhibitor of the hepatitis C virus NS5B polymerase. JOURNAL OF MEDICINAL CHEMISTRY, 54(1), 289–301.
Vancouver
1.
Narjes F, Crescenzi B, Ferrara M, Habermann J, Colarusso S, Ferreira M del R, et al. Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (MK-3281), a potent and orally bioavailable finger-loop inhibitor of the hepatitis C virus NS5B polymerase. JOURNAL OF MEDICINAL CHEMISTRY. 2011;54(1):289–301.
MLA
Narjes, Frank, Benedetta Crescenzi, Marco Ferrara, et al. “Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-loop Inhibitor of the Hepatitis C Virus NS5B Polymerase.” JOURNAL OF MEDICINAL CHEMISTRY 54.1 (2011): 289–301. Print.
@article{1231110,
  abstract     = {Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain Structure activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.},
  author       = {Narjes, Frank and Crescenzi, Benedetta and Ferrara, Marco and Habermann, J{\"o}rg and Colarusso, Stefania and Ferreira, Maria del Rosario and Stansfield, Ian and Mackay, Angela Claire and Conte, Immacolata and Ercolani, Caterina and Zaramella, Simone and Palumbi, Maria-Cecilia and Meuleman, Philip and Leroux-Roels, Geert and Giuliano, Claudio and Fiore, Fabrizio and Marco, Stefania and Baiocco, Paola and Koch, Uwe and Migliaccio, Giovanni and Altamura, Sergio and Laufer, Ralph and De Francesco, Raffaele and Rowley, Michael},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keyword      = {DEPENDENT RNA-POLYMERASE,CHIMERIC HUMAN LIVERS,DE-NOVO INITIATION,UPA-SCID MOUSE,ALLOSTERIC INHIBITORS,NONNUCLEOSIDE INHIBITORS,HCVNS5B POLYMERASE,IN-VIVO,BENZIMIDAZOLE DERIVATIVES,ANTIVIRAL ACTIVITY},
  language     = {eng},
  number       = {1},
  pages        = {289--301},
  title        = {Discovery of (7R)-14-cyclohexyl-7-\{[2-(dimethylamino)ethyl](methyl) amino\}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (MK-3281), a potent and orally bioavailable finger-loop inhibitor of the hepatitis C virus NS5B polymerase},
  url          = {http://dx.doi.org/10.1021/jm1013105},
  volume       = {54},
  year         = {2011},
}

Altmetric
View in Altmetric
Web of Science
Times cited: