azd0914 and Disease-Models--Animal

With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.

Topics: Adult; Animals; Anti-Bacterial Agents; Barbiturates; Disease Models, Animal; DNA Topoisomerases, Type II; Dogs; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Female; Fluoroquinolones; Gonorrhea; Haplorhini; Humans; Isoxazoles; Male; Mice; Microbial Sensitivity Tests; Middle Aged; Models, Molecular; Molecular Conformation; Morpholines; Mutation; Neisseria gonorrhoeae; Oxazolidinones; Rats; Spiro Compounds; Staphylococcal Infections; Staphylococcus aureus; Topoisomerase II Inhibitors; Young Adult

Herein, we report spiropyrimidinetriones (SPTs) incorporating N-linked azole substituents on a benzisoxazole scaffold with improved Gram-positive antibacterial activity relative to previously described analogues. SPTs have an unusual spirocyclic architecture and represent a new antibacterial class of bacterial DNA gyrase and topoisomerase IV inhibitors. They are not cross-resistant to fluoroquinolones and other DNA gyrase/topoisomerase IV inhibitors used clinically. The activity of the SPTs was assessed for DNA gyrase inhibition, and the antibacterial activity across Gram-positive and Gram-negative pathogens with N-linked 1,2,4-triazoles substituted on the 5-position provides the most worthwhile profile. Directed nucleophilic and electrophilic chemistry was developed to vary this 5-position with carbon, nitrogen, or oxygen substituents and explore structure-activity relationships including those around a target binding model. Compounds with favorable pharmacokinetic parameters were identified, and two compounds demonstrated cidality in a mouse model of

Topics: Animals; Anti-Bacterial Agents; Azoles; Disease Models, Animal; DNA Gyrase; Dose-Response Relationship, Drug; Isoxazoles; Mice; Microbial Sensitivity Tests; Molecular Structure; Pyrimidinones; Rats; Rats, Wistar; Spiro Compounds; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Topoisomerase II Inhibitors