Indole 5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase with nanomolar potency in cell-based subgenomic replicons (part 2): Central amino acid linker and right-hand-side SAR studies

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 12, 2011, Pages 3664-3670

  Beaulieu, Pierre L ^a   Chabot, Catherine ^a   Duan, Jianmin ^a   Garneau, Michel ^a   Gillard, James ^a   Jolicoeur, Eric ^a   Poirier, Martin ^a   Poupart, Marc André ^a,b   Stammers, Timothy A ^a   Kukolj, George ^a   Tsantrizos, Youla S ^a,c  

^a BOEHRINGER INGELHEIM CANADA LTD   (Canada)

^b Tranzyme Pharma   (Canada)

^c MCGILL UNIVERSITY   (Canada)

Author keywords

Antiviral; HCV; Hepatitis C virus; Inhibitor; NS5B polymerase; SAR

Indexed keywords

2 (2 PYRIDYL)INDOLE 5 CARBOXAMIDE; ANTIVIRUS AGENT; INDOLE 5 CARBOXAMIDE; NONSTRUCTURAL PROTEIN 5B; RNA POLYMERASE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CELL STRAIN CACO 2; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG SOLUBILITY; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; LIPOPHILICITY; LIVER MICROSOME; MALE; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PHYSICAL CHEMISTRY; RAT; RNA REPLICATION; STRUCTURE ACTIVITY RELATION; TIME TO MAXIMUM PLASMA CONCENTRATION;

ALLOSTERIC REGULATION; AMINO ACID SEQUENCE; AMINO ACIDS; ANIMALS; BENZIMIDAZOLES; CACO-2 CELLS; HEPACIVIRUS; HUMANS; INDOLES; INHIBITORY CONCENTRATION 50; MOLECULAR SEQUENCE DATA; MOLECULAR STRUCTURE; RATS; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS;

EID: 79957852139     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.04.082     Document Type: Article

References (14)

1. Ghany, M. G.; Strader, D. B.; Thomas, D. L.; Seeff, L. B. Hepatology 2009, 49, 1335.
2. Li, H.; Shi, S. T. Future Med. Chem. 2010, 2, 121.
3. Brown, N. A. Expert Opin. Invest. Drugs 2009, 18, 709.
4. (a) Watkins, W. J.; Ray, A. S.; Chong, L. S. Curr. Opin. Drug Disc. Dev. 2010, 13, 441;
5. (b) Legrand-Abravanel, F.; Nicot, F.; Izopet, J. Expert Opin. Invest. Drugs 2010, 19, 963.
6. Beaulieu, P. L. Curr. Opin. Drug Disc. Dev. 2006, 9, 618.
7. Part 1: Beaulieu, P. L. et al., Bioorg. Med. Chem. Lett. (2011), doi:10.1016/j.bmcl.2011.04.082. All α,α-dialkylamino acids used in this work were obtained from commercial sources. See WO 2003/010141 and WO 2004/065367 for experimental procedures detailing the synthesis of diamide inhibitors.
8. JChem 5.0.0 (http://www.chemaxon.com) was used for Log P predictions. The prediction method is based on the algorithm described in Viswanadhan, V. N.; Ghose, A. K.; Revankar, G. R.; Robins, R. K. J. Chem. Inf. Comput. Sci. 1989, 29, 163.
9. Performed on amorphous TFA salts using the 24 h shaking flask method (pH 7.2 phosphate buffer).
10. 1H NMR spectra consistent with expected structures.
11. 50 values were determined as described previously: (a) McKercher, G.; Beaulieu, P. L.; Lamarre, D.; LaPlante, S.; Lefebvre, S.; Pellerin, C.; Thauvette, L.; Kukolj, G. Nucleic Acids Res. 2004, 32, 422;
12. 50 determinations were performed using Huh-7 cells with a stable subgenomic HCV 1b replicon. The HCV RNA levels were normalized to total cellular RNA in this 72 h assay. The quantification of total RNA recovery allowed for an assessment of cellular homeostasis to eliminate the possibility of antiviral activity due to subtle toxic effects. For an overview and basic protocols on the use of HCV replicons, see V. Lohmann, in: H. Tang (Ed.), Methods in Mol. Biol., Hepatitis C: Methods and Protocols, 2009, 510, 145, Second Edition, Humana Press.
13. LaPlante, S. R.; Gillard, J. R.; Jakalian, A.; Aubry, N.; Coulombe, R.; Brochu, C.; Tsantrizos, Y. S.; Poirier, M.; Kukolj, G.; Beaulieu, P. L. J. Am. Chem. Soc. 2010, 132, 15204.
14. Male Sprague-Dawley rats were fasted overnight and dosed by oral gavage at 10 mg/kg using 0.5% methocel and 0.3% Tween-80 as vehicle. Plasma samples from three animals were pooled at each time points (0-8 h) for analysis. Compound detection in plasma samples was performed following liquid-liquid extraction and HPLC analysis using UV detection.