2-(3-Thienyl)-5,6-dihydroxypyrimidine-4-carboxylic acids as inhibitors of HCV NS5B RdRp

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 21, 2009, Pages 6245-6249

  Pacini, Barbara ^a   Avolio, Salvatore ^a   Ercolani, Caterina ^a   Koch, Uwe ^a   Migliaccio, Giovanni ^a   Narjes, Frank ^a   Pacini, Laura ^a   Tomei, Licia ^a   Harper, Steven ^a  

^a IRBM   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

2 ( 3 THIENYL) 5,6 DIHYDROXYPYRIMIDINE 4 CARBOXYLIC ACID; 5, 6 DIHYDROXYPYRIMIDINE 4 CARBOXYLIC ACID; ANTIBIOTIC AGENT; CARBOXYLIC ACID DERIVATIVE; NAPHTHALENE DERIVATIVE; NEOMYCIN; NONSTRUCTURAL PROTEIN 5B; NS5B NONNUCLEOSIDE INHIBITOR; NUCLEOSIDE DERIVATIVE; PYRIMIDINE DERIVATIVE; SULFONYLUREA DERIVATIVE; THIOPHENE DERIVATIVE; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; CELL SURVIVAL; CONTROLLED STUDY; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG POTENCY; ENZYME ACTIVE SITE; ENZYME INHIBITION; GENE MUTATION; GENOTYPE; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; SUBSTITUTION REACTION; VIRUS REPLICATION; VIRUS STRAIN;

ANTIVIRAL AGENTS; CARBOXYLIC ACIDS; CATALYTIC DOMAIN; CELL LINE, TUMOR; COMPUTER SIMULATION; ENZYME INHIBITORS; HEPACIVIRUS; HUMANS; RNA REPLICASE; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

HEPATITIS C VIRUS;

EID: 72049129436     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.06.106     Document Type: Article

References (20)

1. McHutchinson J.G. Am. J. Manag. Care 10 (2004) S21
2. Houghton M., and Abrigani S. Nature 436 (2005) 961
3. Foster G., and Mathurin P. Antivir. Ther. 13 (2008) 3
4. Di Bisceglie A.M., McHutchinson J., and Rice C.M. Hepatology 35 (2002) 224
5. Garber K., and Arbor A. Nat. Biotechnol. 25 (2007) 1379
6. Lahm A., Yagnik A., Tramontano A., and Koch U. Curr. Drug Targets 3 (2002) 281
7. Appel N., Schaller T., Penin F., and Bartenschlager R. J. Biol. Chem. 281 (2006) 9833
8. Beaulieu P.L. Expert Opin. Ther. Patents 19 (2009) 145
9. De Francesco R., Paonessa G., Olsen D.B., Rowley M., Crescenzi B., Habermann J., Narjes F., and Laufer R. Hep DART (2007) Lahaina, Hawaii
10. NCT00623649, USA 2008. Available from: http://clinicaltrials.gov/ct2/show/study/NCT00623649.
11. Rodriguez-Torres, M., Lalezari, J.; Gane, E. J.; DeJesus, E.; Nelson, D. R.; Everson, G.; Jacobson, I.; Reddy, K. R.; McHutchison, J.; Beard, A.; Walker, S.; Symonds, W.; Berrey, M. M. The 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), San Francisco, California, USA, 2008.
12. Summa V., Petrocchi A., Matassa V.G., Taliani M., Laufer R., De Francesco R., Altamura S., and Pace P. J. Med. Chem. 47 (2004) 5336
13. Summa V., Petrocchi A., Pace P., Matassa V.G., De Francesco R., Altamura S., Tomei L., Koch U., and Neuner P. J. Med. Chem. 47 (2004) 14
14. Stansfield I., Avolio S., Colarusso S., Gennari N., Narjes F., Pacini B., Ponzi S., and Harper S. Bioorg. Med. Chem. Lett. 14 (2004) 5085
15. Koch U., Attenni B., Malancona S., Colarusso S., Conte I., Di Filippo M., Harper S., Pacini B., Giomini C., Thomas S., Incitti I., Tomei L., De Francesco R., Altamura S., Matassa V.G., and Narjes F. J. Med. Chem. 49 (2006) 1693
16. a Database Version 11 for details.
17. Koch U., and Narjes F. Curr. Top. Med. Chem. 7 (2007) 1302
18. Due to the typically high plasma protein binding (>99%) and low Caco-2 permeability of 5,6-dihydroxypyrimidine-4-carboxylic acids, a direct correlation between physicochemical properties and cell-based activity was not feasible for the sulfonyl urea compounds. All compounds were judged soluble and are chemically stable in aqueous media over the 4-day duration of the HCV replicon assay.
19. Tomei L., Altamura S., Paonessa G., De Francesco R., and Migliaccio G. Antivir. Chem. Chemother. 16 (2005) 225
20. For details of a similar case in which an in-vitro NS5B enzyme assay failed to recapitulate replicon resistance, and for a more detailed discussion of this topic, see:. Tomei L., Altamura S., Bartholomew L., Bisbocci M., Bailey C., Bosserman M., Celluci A., Forte E., Incitti I., Orsatti L., Koch U., De Francesco R., Olsen D.B., Carroll S.S., and Migliaccio G. J. Virol. 78 (2004) 938