71919-16-9Relevant academic research and scientific papers
Design, synthesis and biological evaluation of water-soluble phenytoin prodrugs considering the substrate recognition ability of human carboxylesterase 1
Haba, Masami,Hosokawa, Masakiyo,Kanayama, Teruhiko,Kondo, Yusuke,Lee, Yeon Joo,Mukai, Kota,Nishio, Kazuki,Takahashi, Masato
, (2020)
Human carboxylesterase 1 (hCES1) is a hydrolase that is mainly expressed in the liver and lung and plays the most important role in the metabolic activation of ester–type prodrugs. In this study, design, synthesis and evaluation of water–soluble phenytoin prodrugs were performed with consideration of the substrate recognition ability of hCES1. The phenytoin prodrugs were synthesized in two steps without column chromatography. It was confirmed that all prodrugs are efficiently converted to phenytoin in a human liver microsome (HLM) solution (up to 54.6 nmol/mg protein/min). Although some of the prodrugs were degraded in strongly basic solution, the solubility of all prodrugs was greater than that of phenytoin in buffer solutions at pH 7.4 and 8.3. Among the synthesized phenytoin prodrugs, the 3,3-dimethylglutarate prodrug was superior in terms of solubility and stability, and it showed solubility of 10 mg/mL or more (phenytoin: 0.1 mg/mL) in a solution of pH 8.3. It was also found that the 3,3-dimethylglutarate prodrug was selectively activated by hCES1 but not hCES2 or arylacetamidodeacetylase.
Phenytoin prodrugs III: Water-soluble prodrugs for oral and/or parenteral use
Varia,Schuller,Sloan,Stella
, p. 1068 - 1073 (2007/10/02)
Various bioreversible derivatives of phenytoin, a poorly water soluble and erratically absorbed drug after both oral and parenteral dosing, were synthesized. Initial evaluation of these expected prodrugs, i.e., their aqueous solubility, cleavage in the presence of various animal tissues, and anticonvulsant activity in mice, confirmed that a number of the derivatives did indeed behave as prodrugs. The more promising prodrugs were the disodium phosphate ester and various amino groups containing acyl esters of 3-(hydroxymethyl)-5,5-diphenylhydantoin.
Derivatives of 5,5-diphenylhydantoin exhibiting enhanced solubility and the therapeutic use thereof
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, (2008/06/13)
Novel derivatives of 5,5-diphenylhydantoin, having the formula: STR1 wherein R is as defined in the specification and claims hereinafter, are disclosed. These compounds exhibit enhanced solubility over diphenylhydantoin per se and find therapeutic usefulness as anticonvulsants, antiepileptics and antiarrhythmics.
