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. © 2010 American Chemical Society.
Discovery of (7 r)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6 H -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 / Narjes, F., Crescenzi, B., Ferrara, M., Habermann, J., Colarusso, S., Del Rosario Rico Ferreira, M., Stansfield, I., Mackay, A.C., Conte, I., Ercolani, C., Zaramella, S., Palumbi, M.-C., Meuleman, P., Leroux-Roels, G., Giuliano, C., Fiore, F., Di Marco, S., Baiocco, P., Koch, U., Migliaccio, G., et al.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 54:1(2011), pp. 289-301. [10.1021/jm1013105]
Discovery of (7 r)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6 H -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
Colarusso S.;Conte I.;Baiocco P.;De Francesco R.;
2011
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. © 2010 American Chemical Society.| File | Dimensione | Formato | |
|---|---|---|---|
|
Narjes_Discovery_2011.pdf
solo gestori archivio
Tipologia:
Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza:
Tutti i diritti riservati (All rights reserved)
Dimensione
2.08 MB
Formato
Adobe PDF
|
2.08 MB | Adobe PDF | Contatta l'autore |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
