BMS-379224, a Water-Soluble Prodrug of Ravuconazole

Y. Ueda, N. Barbour, J. J. Bronson, T. P. Connolly, M. Dali, Q. Gao, J. Golik, S. Huang, T. W. Hudyma, s.-h. Kang, J. Knipe, M. Mathew, J. D. Matiskella, K. Mosure, R. Tejwani, S. Varia, S. Venkatesh, M. Zheng

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Ravuconazole (BMS-207147) licensed from Eisai (ER-30346) is a potent and broad spectrum antifungal agent with exceptional activity against Aspergillus species. It has been under clinical evaluation by BMS as an oral agent, but an intravenous (IV) formulation is desirable for therapy of serious systemic fungal infections such as pulmonary Aspergillus infections. The poor aqueous solubility precludes its development for intravenous administration. Thus, a water-soluble prodrug approach was employed to develop an IV formulation. BMS-379224, a phosphonooxymethyl ether derivative of ravuconazole, was prepared in two steps from ravuconazole. This was evaluated as a potential water-soluble prodrug of ravuconazole. The aqueous solubility of amorphous BMS-379224 was found to be ≷30 mg/mL at pH 7, and BMS-379224 was readily converted to ravuconazole by alkaline phosphatase and liver S9 homogenates . In vivo conversion of BMS-379224 to ravuconazole was also demonstrated upon IV administration in rats, dogs and monkeys. These results indicate BMS-379224 is a promising prodrug of ravuconazole. Synthesis, in vitro / in vivo conversion, and stability of BMS-379224 and other related prodrug will be discussed.

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    • ICAAC 42nd