Abstract
Compound 1 (SNS-314) is a potent and selective Aurora kinase inhibitor that is currently in clinical trials in patients with advanced solid tumors. This communication describes the synthesis of prodrug derivatives of 1 with improved aqueous solubility profiles. In particular, phosphonooxymethyl-derived prodrug 2g has significantly enhanced solubility and is converted to the biologically active parent (1) following iv as well as po administration to rodents.
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Aurora Kinases
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Male
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Mice
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Phenylurea Compounds / chemistry*
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Phenylurea Compounds / pharmacokinetics
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Phenylurea Compounds / pharmacology
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Prodrugs / chemistry*
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Rats
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Rats, Sprague-Dawley
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Solubility
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Thiazoles / chemistry*
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology
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Water / chemistry*
Substances
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Antineoplastic Agents
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Phenylurea Compounds
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Prodrugs
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SNS 314
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Thiazoles
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Water
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Aurora Kinases
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Protein Serine-Threonine Kinases