Clinical data | |
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Other names | AZD0914; ETX0914 |
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Routes of administration | Oral |
Drug class | Antibiotic |
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Pharmacokinetic data | |
Bioavailability | 97.8% |
Metabolism | Hepatic |
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Elimination half-life | 5.3–6.3 h |
Excretion | |
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Chemical and physical data | |
Formula | C22H22FN5O7 |
Molar mass | 487.444 g·mol−1 |
3D model (JSmol) | |
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Zoliflodacin (development codes AZD0914 and ETX0914) is an experimental antibiotic that is being studied for the treatment of infection with Neisseria gonorrhoeae (gonorrhea).[1] It has a novel mechanism of action which involves inhibition of bacterial type II topoisomerases.[2] Zoliflodacin is being developed by Innoviva Specialty Therapeutics, and the drug has demonstrated clinical efficacy equivalent to ceftriaxone in Phase III clinical trials.[3][4]
Zoliflodacin has shown in vitro activity[5] against the following species of bacteria:
Zoliflodacin is primarily active against both Gram-positive, but has activity against fastidious Gram-negative bacteria. It functions by inhibiting DNA gyrase, an enzyme necessary to separate bacterial DNA, thereby inhibiting cell replication.
A high throughput screening campaign aimed at identifying compounds with whole cell antibacterial activity performed at Pharmacia & Upjohn identified compound PNU-286607, a progenitor of Zoliflodacin, as having the desired activity.[6] Subsequent biological profiling of PNU-286607 showed that the compound inhibited DNA synthesis in susceptible bacteria, and analysis of mutants resistant to the compound's activity indicated that these compounds acted on DNA gyrase at a site distinct from that of the fluoroquinolone antibiotics.
Subsequent research at AstraZeneca led to the discovery that the nitroaromatic in PNU-286607 could be replaced with a fused benzisoxazole ring,[7] which allowed for an exploration of different groups at the 3-position of the heterocycle. This work was continued at Entasis Pharmaceuticals where extensive optimization resulted in the discovery of ETX0914,[8] which was renamed Zolifodacin in the course of its clinical development.