Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: synthesis and biological properties |
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Authors: | Ueda Yasutsugu Matiskella John D Golik Jerzy Connolly Timothy P Hudyma Thomas W Venkatesh Srini Dali Mandar Kang Shin-Hong Barbour Nancy Tejwani Ravi Varia Sailesh Knipe Jay Zheng Ming Mathew Marina Mosure Kathy Clark Junius Lamb Lucinda Medin Ivette Gao Qi Huang Stella Chen Chung-Pin Bronson Joanne J |
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Affiliation: | Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Wallingford, CT 06492-7660, USA. yasutsugu.ueda@bms.com |
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Abstract: | Synthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs of ravuconazole are described. The phosphonooxymethyl ether analogue 2 (BMS-379224) and N-phosphonooxymethyl triazolium salt 3 (BMS-315801) were both prepared from ravuconazole (1) and bis-tert-butyl chloromethylphosphate, but under two different conditions. Both derivatives were highly soluble in water and converted to the parent in alkaline phosphatase, and also in vivo (rat). However, BMS-315801 was found to be less stable than BMS-379224 in water at neutral pH. BMS-379224 (2) has proved to be one of the most promising prodrugs of ravuconazole that we tested, and it is currently in clinical evaluation as an intravenous formulation of the broad spectrum antifungal azole, ravuconazole. |
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