title: Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: synthesis and biological properties.
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.
authors.affiliation: Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Wallingford, CT 06492-7660, USA. yasutsugu.ueda@bms.com
authors.forename: Yasutsugu
authors.initials: Y
authors.lastname: Ueda
authors.forename: John D
authors.initials: JD
authors.lastname: Matiskella
authors.forename: Jerzy
authors.initials: J
authors.lastname: Golik
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Connolly
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Hudyma
authors.forename: Srini
authors.initials: S
authors.lastname: Venkatesh
authors.forename: Mandar
authors.initials: M
authors.lastname: Dali
authors.forename: Shin-Hong
authors.initials: SH
authors.lastname: Kang
authors.forename: Nancy
authors.initials: N
authors.lastname: Barbour
authors.forename: Ravi
authors.initials: R
authors.lastname: Tejwani
authors.forename: Sailesh
authors.initials: S
authors.lastname: Varia
authors.forename: Jay
authors.initials: J
authors.lastname: Knipe
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Marina
authors.initials: M
authors.lastname: Mathew
authors.forename: Kathy
authors.initials: K
authors.lastname: Mosure
authors.forename: Junius
authors.initials: J
authors.lastname: Clark
authors.forename: Lucinda
authors.initials: L
authors.lastname: Lamb
authors.forename: Ivette
authors.initials: I
authors.lastname: Medin
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.forename: Stella
authors.initials: S
authors.lastname: Huang
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Chen
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D004355:Drug Stability; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007262:Infusions, Intravenous; D051379:Mice; D008813:Mice, Inbred ICR; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013534:Survival; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D007202:Indicators and Reagents; D011355:Prodrugs; D013844:Thiazoles; D014230:Triazoles; C104066:ER 30346