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Optimization of LpxC Inhibitor Lead Compounds Focusing on Efficacy and Formulation for High Dose Intravenous Administration

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posted on 23.12.2019, 14:34 by Philippe Panchaud, Jean-Philippe Surivet, Stefan Diethelm, Anne-Catherine Blumstein, Jean-Christophe Gauvin, Loïc Jacob, Florence Masse, Gaëlle Mathieu, Azely Mirre, Christine Schmitt, Michel Enderlin-Paput, Roland Lange, Carmela Gnerre, Swen Seeland, Charlyse Herrmann, Hans H. Locher, Peter Seiler, Daniel Ritz, Georg Rueedi
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.