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

详细信息    查看全文

• 作者：Hardwin O鈥橠owd ; Dean E. Shannon ; Kishan R. Chandupatla ; Vaishali Dixit ; Juntyma J. Engtrakul ; Zhengqi Ye ; Steven M. Jones ; Colleen F. O鈥橞rien ; David P. Nicolau ; Pamela R. Tessier ; Jared L. Crandon ; Bin Song ; Dainius Macikenas ; Brian L. Hanzelka ; Arnaud Le Tiran ; Youssef L. Bennani ; Paul S. Charifson ; Anne-Laure Grillot
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：July 9, 2015
• 年：2015
• 卷：6
• 期：7
• 页码：822-826
• 全文大小：282K
• ISSN：1948-5875

文摘

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.