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ACS Med Chem Lett. 2015 Jun 22;6(7):822-6. doi: 10.1021/acsmedchemlett.5b00196. eCollection 2015 Jul 9.

Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV.

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Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
Center for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, Connecticut 06102, United States.
Vertex Pharmaceuticals Incorporated , 2500 Crosspark Road, Bioventures Center, Coralville, Iowa 52241, United States.
Vertex Pharmaceuticals Incorporated , 275 Boulevard Armand Frappier, Laval, QC H7V 4A7, Canada.


Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.


DNA gyrase; Prodrug; topoisomerase IV; water soluble

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