Novel HCV NS5B polymerase inhibitors derived from 4-(1′,1′-dioxo-1′,4′-dihydro-1′λ6-benzo[1′,2′,4′]thiadiazin-3′-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 1: Exploration of 7′-substitution of benzothiadiazine

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 4, 2008, Pages 1413-1418

  Zhou, Yuefen ^a   Webber, Stephen E ^a   Murphy, Douglas E ^a   Li, Lian Sheng ^a   Dragovich, Peter S ^a   Tran, Chinh V ^a   Sun, Zhongxiang ^a   Ruebsam, Frank ^a   Shah, Amit M ^a   Tsan, Mei ^a   Showalter, Richard E ^a   Patel, Rupal ^a   Li, Bin ^a   Zhao, Qiang ^a   Han, Qing ^a   Hermann, Thomas ^a   Kissinger, Charles R ^a   LeBrun, Laurie ^a   Sergeeva, Maria V ^a   Kirkovsky, Leo ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

5 Hydroxy 3(2H) pyridazinone derivatives; Hepatitis C virus (HCV); Non nucleoside NS5B inhibitors; Pyridazinones; RNA dependent RNA polymerase (RdRp); Small molecule; Structure based design

Indexed keywords

5 HYDROXY 3(2H) PYRIDAZINONE DERIVATIVE; BENZOTHIADIAZINE DERIVATIVE; ENZYME INHIBITOR; NONSTRUCTURAL PROTEIN 5B; PYRIDAZINONE DERIVATIVE; RNA DIRECTED RNA POLYMERASE; UNCLASSIFIED DRUG;

ARTICLE; DRUG SYNTHESIS; GENOTYPE; HEPATITIS C VIRUS; NONHUMAN; STRUCTURE ACTIVITY RELATION;

BENZOTHIADIAZINES; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; DRUG STABILITY; ENZYME INHIBITORS; HUMANS; HYDROGEN BONDING; INHIBITORY CONCENTRATION 50; MICROSOMES, LIVER; MODELS, MOLECULAR; PYRIDAZINES; RNA REPLICASE; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS;

EID: 38949121259     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.01.007     Document Type: Article

References (30)

1. Kim W.R. Hepatology 36 (2002) 30
2. Alter M.J., Kruszon-Moran D., Nainan O.V., McQuillan G.M., Gao F., Moyer L.A., Kaslow R.A., and Margolis H.S. N. Engl. J. Med. 341 (1999) 556
3. Hoofnagle J.H., and Seeff L.B. N. Engl. J. Med. 355 (2007) 2444
4. Kolykhalov A.A., Agapov E.V., Blight K.J., Mihalik K., Feinstone S.M., and Rice C.M. Science 277 (1997) 570
5. Koch U., and Narjes F. Curr. Top. Med. Chem. 7 (2007) 1302
6. Pierra C., Benzaria S., Amador A., Moussa A., Mathieu S., Storer R., and Gosselin G. Nucleosides, Nucleotides Nucleic Acids 24 (2005) 767
7. Pierra C., Amador A., Benzaria S., Cretton-Scott E., D'Amours M., Mao J., Mathieu S., Moussa A., Bridges E.G., Standring D.N., Sommadossi J.-P., Storer R., and Gosselin G. J. Med. Chem. 49 (2006) 6614
8. Conference report from the 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), October 27-31, 2006, Boston, MA, http://www.natap.oeg/2006/AASLD/AASLD_04.htm.
9. Slater M.J., et al. J. Med. Chem. 50 (2007) 897
10. Conference report from 42nd Meeting of the European Association for the Study of Liver Diseases (EASL), April 11-15, 2007, Barcelona, Spain, http://www.natap.org/2007/EASL/EASL_13.htm;.
11. Conference report from Digestive Disease Week, Los Angeles, May 21-24, 2006, http://www.natap.org/2006/DDW/DDW_18.htm.
12. Dhanak D., et al. J. Biol. Chem. 277 (2002) 38322
13. Evans K.A., Chai D., Graybill T.L., Burton G., Sarisky R.T., Lin-Goerke J., Johnston V.K., and Rivero R.A. Bioorg. Med. Chem. Lett. 16 (2006) 2205
14. Blake, J. F.; Fell, J. B.; Fischer, J. P.; Hendricks, R. T.; Spencer, S. R.; Stengel, P. J. WO2006117306, 2006.
15. Pratt J.K., Donner P., McDaniel K.F., Maring C.J., Kati W.M., Mo H., Middleton T., Liu Y., Ng T., Xie Q., Zhang R., Montgomery D., Molla A., Kempf D.J., and Kohlbrenner W. Bioorg. Med. Chem. Lett. 15 (2005) 1577
16. Hutchinson, D. K. et al. U.S. Patent US2005107364, bf 2005.
17. Tedesco R., Shaw A.N., Bambal R., Chai D., Concha N.O., Darcy M.G., Dhanak D., Fitch D.M., Gates A., Gerhardt W.G., Halegoua D.L., Han C., Hofmann G.A., Johnston V.K., Kaura A.C., Liu N., Keenan R.M., Goerke J.L., Sarisky R.T., Wiggall K.J., Zimmerman M.N., and Duffy K.J. J. Med. Chem. 49 (2006) 971
18. 2 at pH 7.6, and inhibitors at concentrations of 2-10 mM. Diffraction data were collected to a resolution of 2.65 Å for compound 3 and 2.3 Å for compound 8e. Diffraction data for 8e were collected on beamline 14IDB at the Advanced Photon Source at Argonne National Laboratory. Crystal structures discussed in this paper have been deposited in the Protein Databank (www.rcsb.org) with entry codes: 3BSC and 3BR9. Full details of structure determination are given in the respective PDB entries.
19. The O-atom at the 5-position of the pyridazin-3-one in Figure 3 was arbitrarily drawn in the protonated form. The precise extent of the protonation was not determined.
20. The procedures for the synthesis of 5-hydroxy-3(2H)-pyridazinone derivatives (2) using methods A and B (and other methods) are described in Zhou, Y.; Li, L.-S.; Webber, S. E. WO06066079A2, 2006.
21. The procedures for the synthesis of pyridazinone esters 4 and hydrazones 6 are described in. Li L.-S., Zhou Y., Zhao J., Dragovich P.S., Stankovic N.S., Bertolini T.M., Murphy D.E., Sun Z., Tran C.V., Ayida B.K., Ruebsam F., and Webber S.E. Synthesis (2007) 3301
22. Murphy D.E., Dragovich P.S., Ayida B.K., Bertolini T.M., Li L.-S., Ruebsam F., Stankovic N.S., Sun Z., and Zhou Y. Tetrahedron Lett. 49 (2008) 811
23. 3 is OMe were prepared using modified literature methods as described in. Fitch M.D., Evans K.A., Chai D., and Duffy K.J. Org. Lett. 7 (2005) 5521
24. Kovalenko S.N., Chernykh V.P., Shkarlat A.E., Ukrainets I.V., Gridasov V.I., and Rudnev S.A. Chem. Heterocycl. Compd. (Engl. Transl.) 34 (1999) 791
25. 1H NMR and LC-MS data (≥95% HPLC purity). They are arbitrarily drawn in one tautomer form.
26. 50 data is 32% from the mean value.
27. 50 data is 56% from the mean value.
28. 1/2 values from multiple replicate experiments on a representative compound gave a 16% standard deviation from the mean value.
29. Conradi R.A., Hilgers A.R., Ho N.F.H., and Burton P.S. Pharm. Res. 9 (1992) 435
30. Zhou Y., Li L.-S., Dragovich P.S., Murphy D.E., Tran C.V., Ruebsam F., Webber S.E., Shah A.M., Tsan M., Averill A., Showalter R.E., Patel R., Han Q., Zhao Q., Hermann T., Kissinger C.R., LeBrun L., and Sergeeva M.V. Bioorg. Med. Chem. Lett. 18 (2008) 1419