Optimization of LpxC Inhibitor Lead Compounds Focusing on Efficacy and Formulation for High Dose Intravenous Administration
| Autor: | Michel Enderlin-Paput, Swen Seeland, A.-C. Blumstein, Daniel Ritz, Peter Seiler, R. Lange, Jean-Philippe Surivet, Christine Schmitt, F. Masse, Jean-Christophe Gauvin, S. Diethelm, L. Jacob, Charlyse Herrmann, Carmela Gnerre, Hans H. Locher, G. Mathieu, Azely Mirre, Georg Rueedi, Philippe Panchaud |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Drug
media_common.quotation_subject Microbial Sensitivity Tests Pharmacology Hydroxamic Acids 01 natural sciences Amidohydrolases 03 medical and health sciences Mice In vivo Drug Discovery Gram-Negative Bacteria Animals Solubility Enzyme Inhibitors Lead (electronics) Escherichia coli Infections 030304 developmental biology media_common 0303 health sciences Molecular Structure Chemistry 0104 chemical sciences Anti-Bacterial Agents Rats 010404 medicinal & biomolecular chemistry Hepatocytes Molecular Medicine Administration Intravenous |
| Zdroj: | Journal of medicinal chemistry. 63(1) |
| ISSN: | 1520-4804 |
| Popis: | LpxC inhibitors were optimized starting from lead compounds with limited efficacy and solubility and with the goal to provide new options for the treatment of serious infections caused by Gram-negative pathogens in hospital settings. To enable the development of an aqueous formulation for intravenous administration of the drug at high dose, improvements in both solubility and antibacterial activity in vivo were prioritized early on. This lead optimization program resulted in the discovery of compounds such as 13 and 30, which exhibited high solubility and potent efficacy against Gram-negative pathogens in animal infection models. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|