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A new structural alert for benzimidazoles: 2,6-dimethylphenyl substituents increase mutagenic potential and time-dependent CYP3A4 inhibition risk |
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| Authors: | Kwak Youngshin Coppola Gary Forster Cornelia J Gilmore Thomas A Gong Yongjin Kanter Aaron Neubert Alan Stroup Bryan Szklennik Paul Glowienke Susanne Stadelmann Pascal Bell Leslie Bickford Shari Gangl Eric Gunduz Mithat Jain Monish Zhan Jenny Serrano-Wu Michael H |
| Affiliation: | a Global Discovery Chemistry, Cambridge, MA 02139, United States b Translational Sciences, Basel, Switzerland c Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, United States |
| Abstract: | A series of 2-[(2,6)-dimethylphenyl]benzimidazole analogs displayed strong potential for mutagenicity following metabolic activation in either TA98 or TA100 Salmonella typhimurium strains. The number of revertants was significantly reduced by replacing the 2,6-dimethylphenyl group with a 2,6-dichlorophenyl moiety. Time-dependent CYP3A4 inhibition was also observed with a compound containing a 2-[(2,6)-dimethylphenyl] benzimidazole ring, implying risk for this scaffold to generate reactive metabolites. |
| Keywords: | Benzimidazole Mutagenicity Time-dependent CYP3A4 inhibition |
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