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

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.