Journal of Medicinal Chemistry · 2019 · 17 citations · 7 references
PharmacyMedicinal ChemistryPharmacologyDrug DiscoveryLead OptimizationPharmaceutical FormulationHit-to-lead OptimizationLead Compound DesignLead DiscoveryPharmacokinetic OptimizationPotency OptimizationSolubility OptimizationAntibacterial Drug SelectionCompound Potency OptimizationEarly-stage Drug Discovery OptimizationHigh SolubilityLead Compound OptimizationLead Compound PrioritizationNovel Antibacterial Drug DiscoverySolubility
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.
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Oxetanes in Drug Discovery: Structural and Synthetic Insights
Georg Wuitschik, Erick M. Carreira, Björn Wagner et al. · Journal of Medicinal Chemistry · 2010 · 405 citations