Second-generation antibacterial benzimidazole ureas: discovery of a preclinical candidate with reduced metabolic liability
| Autor: | Marc Jacobs, Hardwin O'dowd, Shannon Dean, Paul S. Charifson, Tim Doyle, Trudy H. Grossman, Vaishali Dixit, Brian Boucher, Pan Li, Nigel Ewing, Youssef L. Bennani, Emanuele Perola, Yusheng Liao, Anne-Laure Grillot, Emmanuelle Sizensky, Tiansheng Wang, Lauffer David J, Arnaud Le Tiran, Brian L. Hanzelka, Elaine Krueger, Waal Nathan D, Jerry Tanoury, Shengkai Liao, Steve Ronkin, Qing Tang, Jones Steven |
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| Rok vydání: | 2014 |
| Předmět: |
DNA Topoisomerase IV
Benzimidazole Topoisomerase IV Microbial Sensitivity Tests DNA gyrase chemistry.chemical_compound Structure-Activity Relationship In vivo Drug Discovery Structure–activity relationship Moiety Animals Humans Topoisomerase II Inhibitors Urea Enzyme Inhibitors biology Chemistry Anti-Bacterial Agents Biochemistry DNA Gyrase Drug Design biology.protein Microsomes Liver Molecular Medicine Benzimidazoles Antibacterial activity |
| Zdroj: | Journal of medicinal chemistry. 57(21) |
| ISSN: | 1520-4804 |
| Popis: | Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters. To identify second-generation aminobenzimidazole ureas devoid of reactive metabolite formation potential, we implemented a metabolic shift strategy, which focused on shifting metabolism away from the urea moiety by introducing metabolic soft spots elsewhere in the molecule. Aminobenzimidazole urea 34, identified through this strategy, exhibits similar antibacterial activity as that of 3 and did not label liver proteins in vivo, indicating reduced/no potential for reactive metabolite formation. |
| Databáze: | OpenAIRE |
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