A new structural alert for benzimidazoles: 2,6-Dimethylphenyl substituents increase mutagenic potential and time-dependent CYP3A4 inhibition risk

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 5, 2011, Pages 1422-1424

  Kwak, Youngshin ^a   Coppola, Gary ^a   Forster, Cornelia J ^a   Gilmore, Thomas A ^a   Gong, Yongjin ^a   Kanter, Aaron ^a   Neubert, Alan ^a   Stroup, Bryan ^a   Szklennik, Paul ^a   Glowienke, Susanne ^b   Stadelmann, Pascal ^b   Bell, Leslie ^c   Bickford, Shari ^c   Gangl, Eric ^c   Gunduz, Mithat ^c   Jain, Monish ^c   Zhan, Jenny ^c   Serrano Wu, Michael H ^a  

^a Global Discovery Chemistry   (United States)

^b Translational Sciences   (Switzerland)

^c NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

Benzimidazole; Mutagenicity; Time dependent CYP3A4 inhibition

Indexed keywords

2 [(2,6) DIMETHYLPHENYL]BENZIMIDAZOLE; BENZIMIDAZOLE DERIVATIVE; CYTOCHROME P450 3A4; UNCLASSIFIED DRUG;

AMES TEST; ARTICLE; CONTROLLED STUDY; DRUG STRUCTURE; ENZYME INHIBITION; GENETIC RISK; GENOTOXICITY; METABOLIC ACTIVATION; MUTAGENICITY; NONHUMAN; REVERTANT; SALMONELLA TYPHIMURIUM; SUBSTITUTION REACTION;

ALBENDAZOLE; ANTHELMINTICS; BENZIMIDAZOLES; CYTOCHROME P-450 CYP3A; MUTAGENICITY TESTS; MUTAGENS; SALMONELLA TYPHIMURIUM; TIME FACTORS;

SALMONELLA TYPHIMURIUM;

EID: 79951723616     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.01.023     Document Type: Article

References (19)

1. S. Bhattacharya, and P. Chaudhuri Curr. Top. Med. Chem. 15 2008 1762
2. N.H. Hauel, H. Nar, H. Priepke, U. Ries, J.M. Stassen, and W. Wienen J. Med. Chem. 45 2002 1757
3. K.F. Croom, and L.J. Scott Drugs 65 2005 2129
4. R.D. Carpenter, P.B. Debert, and K.S. Lam J. Comb. Chem. 8 2006 907
5. A. Kamal, K.L. Reddy, and V. Devaiah Mini-Rev. Med. Chem. 6 2006 71
6. J.P. Seiler Mutat. Res. 32 1975 151
7. J.P. Seiler Mutat. Res. 13 1975 635
8. M.D. Mudry de Pargament, M. Labal de Vinuesa, and I. Larripa Mutat. Res. 188 1987 1
9. J. Velik, V. Baliharova, and J. Fink-Gremmels Res. Vet. Sci. 76 2004 95
10. P.L. Beaulieu, J. Gillard, and D. Bykowski Bioorg. Med. Chem. Lett. 16 2006 4987
11. B. Tekiner-Gulbas, O. Temiz-Arpaci, and E. Oksuzoglu SAR QSAR Environ. Res. 18 2007 251
12. J.L. Bolton, M.A. Trush, and T.M. Penning Chem. Res. Toxicol. 13 2000 135
13. B. Ames, L. Haroun, and A.W. Andrews Mutat. Res. 62 1979 393
14. K. Mortelmans, and E. Zeiger Mutat. Res. 455 2000 29
15. K. Takahashi, T. Kaiya, and Y. Kawazoe Mutat. Res. 187 1987 191
16. 1H NMR (MeOD): δ 8.49 (s, broad, 0.5 H), 8.40 (q, 2H), 8.36 (s, broad, 0.5H), 8.06 (d, broad, J = 8.59 Hz, 1H), 7.93-7.88 (m, 2H), 7.72 (t, 2H), 7.63-7.55 (m, 3H), 7.52 (t, 1H).
17. G. Cruciani, E. Carosati, and B. De Boeck J. Med. Chem. 48 2005 6970
18. K. Grime, J. Bird, and D. Ferguson Eur. J. Pharm. Sci. 36 2009 175
19. R.J. Riley, K. Grime, and R. Weaver Expert Opin. Drug. Metab. Toxicol. 3 2007 51