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-31580...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2003-11, Vol.13 (21), p.3669-3672 |
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| creator | UEDA, Yasutsugu MATISKELLA, John D VARIA, Sailesh KNIPE, Jay MING ZHENG MATHEW, Marina MOSURE, Kathy CLARK, Junius LAMB, Lucinda MEDIN, Ivette QI GAO HUANG, Stella GOLIK, Jerzy CHEN, Chung-Pin BRONSON, Joanne J CONNOLLY, Timothy P HUDYMA, Thomas W VENKATESH, Srini DALI, Mandar KANG, Shin-Hong BARBOUR, Nancy TEJWANI, Ravi |
| description | 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. |
| doi_str_mv | 10.1016/j.bmcl.2003.08.029 |
| format | Article |
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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.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2003.08.029</identifier><identifier>PMID: 14552754</identifier><language>eng</language><publisher>Oxford: Elsevier</publisher><subject>Animals ; Antibiotics. Antiinfectious agents. 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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.</description><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antifungal agents</subject><subject>Antifungal Agents - chemical synthesis</subject><subject>Antifungal Agents - pharmacokinetics</subject><subject>Antifungal Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Candidiasis - drug therapy</subject><subject>Candidiasis - microbiology</subject><subject>Drug Stability</subject><subject>Female</subject><subject>Humans</subject><subject>Indicators and Reagents</subject><subject>Infusions, Intravenous</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Pharmacology. Drug treatments</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - pharmacokinetics</subject><subject>Prodrugs - pharmacology</subject><subject>Rats</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><subject>Survival</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - pharmacokinetics</subject><subject>Thiazoles - pharmacology</subject><subject>Triazoles - chemical synthesis</subject><subject>Triazoles - pharmacokinetics</subject><subject>Triazoles - pharmacology</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtr3DAUhUVpaSZJ_0AXRZt2FbtXb6u7EPqCQAptoDshydKMB9tyJbtk-uvrSQayuhz4zrnwIfSWQE2AyI_72g2-rykAq6GpgeoXaEO45BXjIF6iDWgJVaP57zN0XsoegHDg_DU6I1wIqgTfoOXHLpVpl8aUHg5DmHeHHk85tXnZFpwinncBu5xsi8sU_JyXAdtx7uIybm2P7b_Uhyuc7d_Fp_ExfcI_D-PaKl1ZyRa7LvVp23n7uDuFPHehXKJX0fYlvDndC3T_5fOvm2_V7d3X7zfXt5VnWs0VF5pwByIo7R0lwQLRytEmiqgZ8z42rCUeqApS8jbqoKVjRFpKWtowZ9kF-vC0u77-s4Qym6ErPvS9HUNailFCSSKVWEH6BPqcSskhmil3g80HQ8AcZZu9Oco2R9kGGrPKXkvvTuuLG0L7XDnZXYH3J8CWVUDMdvRdeeYEUVJwzv4DW8uMGg</recordid><startdate>20031103</startdate><enddate>20031103</enddate><creator>UEDA, Yasutsugu</creator><creator>MATISKELLA, John D</creator><creator>VARIA, Sailesh</creator><creator>KNIPE, Jay</creator><creator>MING ZHENG</creator><creator>MATHEW, Marina</creator><creator>MOSURE, Kathy</creator><creator>CLARK, Junius</creator><creator>LAMB, Lucinda</creator><creator>MEDIN, Ivette</creator><creator>QI GAO</creator><creator>HUANG, Stella</creator><creator>GOLIK, Jerzy</creator><creator>CHEN, Chung-Pin</creator><creator>BRONSON, Joanne J</creator><creator>CONNOLLY, Timothy P</creator><creator>HUDYMA, Thomas W</creator><creator>VENKATESH, Srini</creator><creator>DALI, Mandar</creator><creator>KANG, Shin-Hong</creator><creator>BARBOUR, Nancy</creator><creator>TEJWANI, Ravi</creator><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20031103</creationdate><title>Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: Synthesis and biological properties</title><author>UEDA, Yasutsugu ; MATISKELLA, John D ; VARIA, Sailesh ; KNIPE, Jay ; MING ZHENG ; MATHEW, Marina ; MOSURE, Kathy ; CLARK, Junius ; LAMB, Lucinda ; MEDIN, Ivette ; QI GAO ; HUANG, Stella ; GOLIK, Jerzy ; CHEN, Chung-Pin ; BRONSON, Joanne J ; CONNOLLY, Timothy P ; HUDYMA, Thomas W ; VENKATESH, Srini ; DALI, Mandar ; KANG, Shin-Hong ; BARBOUR, Nancy ; TEJWANI, Ravi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c397t-45914b05e79cb21ea0197b28f5f933ccf83d1c027e664df9e96b316a21d283ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Antibiotics. 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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.</abstract><cop>Oxford</cop><pub>Elsevier</pub><pmid>14552754</pmid><doi>10.1016/j.bmcl.2003.08.029</doi><tpages>4</tpages></addata></record> |
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| subjects | Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antifungal agents Antifungal Agents - chemical synthesis Antifungal Agents - pharmacokinetics Antifungal Agents - pharmacology Biological and medical sciences Candidiasis - drug therapy Candidiasis - microbiology Drug Stability Female Humans Indicators and Reagents Infusions, Intravenous Medical sciences Mice Mice, Inbred ICR Pharmacology. Drug treatments Prodrugs - chemical synthesis Prodrugs - pharmacokinetics Prodrugs - pharmacology Rats Solubility Structure-Activity Relationship Survival Thiazoles - chemical synthesis Thiazoles - pharmacokinetics Thiazoles - pharmacology Triazoles - chemical synthesis Triazoles - pharmacokinetics Triazoles - pharmacology |
| title | Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: Synthesis and biological properties |
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