Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: synthesis and biological properties.
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.
Ueda
Yasutsugu
Y
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Wallingford, CT 06492-7660, USA. yasutsugu.ueda@bms.com
Matiskella
John D
JD
Golik
Jerzy
J
Connolly
Timothy P
TP
Hudyma
Thomas W
TW
Venkatesh
Srini
S
Dali
Mandar
M
Kang
Shin-Hong
SH
Barbour
Nancy
N
Tejwani
Ravi
R
Varia
Sailesh
S
Knipe
Jay
J
Zheng
Ming
M
Mathew
Marina
M
Mosure
Kathy
K
Clark
Junius
J
Lamb
Lucinda
L
Medin
Ivette
I
Gao
Qi
Q
Huang
Stella
S
Chen
Chung-Pin
CP
Bronson
Joanne J
JJ
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*
D000935:Antifungal Agents; D007202:Indicators and Reagents; D011355:Prodrugs; D013844:Thiazoles; D014230:Triazoles; C104066:ER 30346