Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: Discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 4, 2004, Pages 967-971

  Beaulieu, Pierre L ^a   Bös, Michael ^a   Bousquet, Yves ^a   DeRoy, Patrick ^a,b   Fazal, Gulrez ^a   Gauthier, Jean ^a   Gillard, James ^a   Goulet, Sylvie ^a   McKercher, Ginette ^a   Poupart, Marc André ^a   Valois, Serge ^a   Kukolj, George ^a  

^a BOEHRINGER INGELHEIM CANADA LTD   (Canada)

^b UNIVERSITÉ DE SHERBROOKE   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

BENZIMIDAZOLE DERIVATIVE; ENZYME INHIBITOR; NS5B POLYMERASE; RNA POLYMERASE; UNCLASSIFIED DRUG;

ARTICLE; CONCENTRATION RESPONSE; DRUG CONFORMATION; DRUG POTENCY; DRUG SPECIFICITY; DRUG STRUCTURE; ENZYME INHIBITION; HEPATITIS C VIRUS; INHIBITION KINETICS; MAMMAL; MOLECULAR SIZE; STRUCTURE ANALYSIS;

HEPATITIS C VIRUS; MAMMALIA;

EID: 10744227250     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2003.12.032     Document Type: Article

References (22)

1. Di Bisceglie A.M. Lancet. 351:1998;351.
2. Choo Q.-L., Kuo G., Weiner A.J., Overby L.R., Bradley D.W., Houghton M. Science. 244:1989;359.
3. (c) World Health Organization; Hepatitis C. Seroprevalance of hepatitis C virus (HCV) in a population sample, Wkly. Epidemiol. Rec. 1996, 71, 346.
4. Wasley A., Alter M.J. Semin. Liver Dis. 20:2000;1.
5. Di Bisceglie A.M., Hoofnagle J.H. Hepatology. 36:2002;S121.
6. Chandler G. Hepatology. 36:2002;S135.
7. Beaulieu P.L., Llinàs-Brunet M. Curr. Med. Chem.-Anti-Infective Agents. 1:2002;163.
8. For recent disclosures of other non-nucleoside HCV NS5B polymerase inhibitors, see: Dhanak D., Duffy K.J., Johnston V.K., Lin-Goerke J., Darcy M., Shaw A.N., Gu B., Silverman C., Gates A.T., Nonnemacher M.R., Earnshaw D.L., Casper D.J., Kaura A., Baker A., Greenwood C., Gutshall L.L., Maley D., DelVecchio A., Macarron R., Hofmann G.A., Alnoah Z., Cheng H.-Y., Chan G., Khandekar S., Keenan R.M., Sarisky R.T. J. Biol. Chem. 277:2002;38322.
9. Chan L., Reddy T.J., Proulx M., Das S.K., Pereira O., Wang W., Siddiqui A., Yannopoulos C.G., Poisson C., Turcotte N., Drouin A., Alaoui-Ismaili M.H., Bethell R., Hamel M., L'Heureux L., Bilimoria D., Nguyen-Ba N. J. Med. Chem. 46:2003;1283.
10. Beaulieu P.L., Bös M., Bousquet Y., Fazal G., Gauthier J., Gillard J., Goulet S., LaPlante S., Poupart M.-A., Lefebvre S., McKercher G., Pellerin C., Austel V., Kukolj G. Bioorg. Med. Chem. Lett. 14:2004;119.
11. McKercher, G.; Beaulieu, P. L.; Lamarre, D.; LaPlante, S.; Lefebvre, S.; Pellerin, C.; Thauvette, L.; Kukolj, G. Nucleic Acid Res. 2004, 32, in press.
12. Lohmann V., Körner F., Koch J.O., Herian U., Theilmann L., Bartenschlager R. Science. 285:1999;110.
13. The in vitro enzymatic assay used to evaluate the potential of compounds as inhibitors of HCV polymerase is described in reference 6 and US patents 6,448,281 B1 and 6,479,508 B1 (2002) to Boehringer Ingelheim (Canada) Ltd.
14. NMR studies on the bioactive conformation of this class of inhibitors when bound to NS5B will be reported separately: LaPlante, S. et al. (manuscript in preparation).
15. The solubility of compounds 4 and 10 was measured in aqueous pH 7. 2 phosphate buffer and were found to be 5 μg/mL and >991 μg/mL, respectively. The low solubility of neutral molecules such as 2-4 and others (not shown) was considered a liability at this stage, in terms of establishing solid SAR patterns. For this reason, optimization studies were pursued in the more soluble carboxylic acid class.
16. 50=0.11 μM) and a substantial increase in lipophilicity resulting from the removal of ionizable functions (log D=3.07, solubility=0. 6 μg/mL in pH 7.2 phosphate buffer), only 30% inhibition was measured at the highest non-cytotoxic concentration (3.4 μM). No hydrolysis of the methyl ester was detected under assay conditions.
17. Beaulieu P.L., Haché B., von Moos E. Synthesis. 2003;1683.
18. TBTU was used as coupling reagent: Knorr R., Trzeciak A., Bannwarth W., Gillessen D. Tetrahedron Lett. 30:1989;1927.
19. Saponification of the α-ester group was found to proceed with minimal racemization as determined by HPLC analysis on a chiral support.
20. Irie K., Ishida A., Nakamura T., Oh-Ishi T. Chem. Pharm. Bull. 32:1984;2126.
21. Dua R.K., Phillips R.S. Tetrahedron Lett. 33:1992;29.
22. Sisido K., Nabiko K., Isida T. Organomet. Chem. 33:1971;337.