Abstract
A convergent total synthesis platform led to the discovery of TP-2758 from a series of novel 7-methoxy-8-heterocyclyl tetracycline analogs. TP-2758 demonstrated high in vitro potency against key Gram-negative pathogens including extended spectrum β-lactamases- and carbapenemase-producing Enterobacteriaceae and Acinetobacter spp. strains. This compound was efficacious when administered either intravenously or orally in multiple murine infection models and displayed a favorable preclinical pharmacological profile supporting its advancement into clinical development.
MeSH terms
-
Acinetobacter / drug effects
-
Administration, Intravenous
-
Administration, Oral
-
Animals
-
Anti-Bacterial Agents / chemical synthesis*
-
Anti-Bacterial Agents / pharmacokinetics
-
Anti-Bacterial Agents / pharmacology*
-
Bacterial Proteins / antagonists & inhibitors
-
Bacterial Proteins / genetics
-
Drug Discovery
-
Drug Resistance, Multiple, Bacterial / drug effects
-
Enterobacteriaceae / drug effects
-
Gram-Negative Bacteria / drug effects*
-
Gram-Negative Bacterial Infections / microbiology
-
Macaca fascicularis
-
Microbial Sensitivity Tests
-
Rats
-
Rats, Sprague-Dawley
-
Structure-Activity Relationship
-
Tetracyclines / chemical synthesis*
-
Tetracyclines / pharmacokinetics
-
Tetracyclines / pharmacology*
-
beta-Lactamase Inhibitors / chemical synthesis
-
beta-Lactamase Inhibitors / pharmacology
-
beta-Lactamases / genetics
Substances
-
Anti-Bacterial Agents
-
Bacterial Proteins
-
Tetracyclines
-
beta-Lactamase Inhibitors
-
beta-Lactamases
-
carbapenemase