Heterocyclyl tetracyclines. 2. 7-Methoxy-8-pyrrolidinyltetracyclines: discovery of TP-2758, a potent, orally efficacious antimicrobial against Gram-negative pathogens

• DOI: 10.1038/ja.2017.86
• Publication Date: 2017-07-26T13:05:54Z
• Authors: Cuixiang Sun; Yonghong Deng; Diana K Hunt; Corey Fyfe; Chi-Li Chen; Roger B Clark; Trudy H Grossman; Joyce A Sutcliffe; Xiao-Yi Xiao
• Keywords: Acinetobacter; Administration, Oral; Microbial Sensitivity Tests; 01 natural sciences; beta-Lactamases; Anti-Bacterial Agents; Rats; 0104 chemical sciences; 3. Good health; Rats, Sprague-Dawley; Macaca fascicularis; Structure-Activity Relationship; Bacterial Proteins; Enterobacteriaceae; Tetracyclines; Drug Resistance, Multiple, Bacterial; Drug Discovery; Gram-Negative Bacteria; Animals; Administration, Intravenous; Gram-Negative Bacterial Infections; beta-Lactamase Inhibitors

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.