Abstract
Antedrug approach of the corticosteroids has been described as a fundamentally sound approach for the development of safer anti-inflammatory steroids devoid of systemic side effects. In our continued efforts under the antedrug paradigm, we have recently extended this effort to synthesize the 21-thioalkylether derivatives of methyl 16- prednisolonecarboxylates. The 21-mesylate of the methyl-16-perdnisolonecarboxylates and 9-fluoro-17-dehydro methyl 16-prednisolonecarboxylate were reacted with Na-thioalkoxides to furnish the desired thioalkylethers in 60-75% yields. These newly synthesized thioalkylether steroid series were tested for their in vitro metabolism and corticosteroid receptor binding affinity. They were metabolized in predictable manner to inactive 16-carboxylic acids. All the newly synthesized antedrugs showed lowered glucocorticoid receptor binding affinity than prednisolone indicating that the replacement of the 21-OH function with thioalkylether of the 16-prednisolone carboxylate esters decreases their receptor binding affinity.
Keywords: Antedrug, thioalkylether, anti-inflammatory steroids, dissociated steroids, receptor binding
Medicinal Chemistry
Title: New Steroidal Anti-Inflammatory Antedrugs: 21-Thioalkylether Derivatives of Methyl 16-Prednisolone Carboxylates
Volume: 3 Issue: 6
Author(s): M. Omar F. Khan, Kwan K. Park, Sharye N. Glynn and Henry J. Lee
Affiliation:
Keywords: Antedrug, thioalkylether, anti-inflammatory steroids, dissociated steroids, receptor binding
Abstract: Antedrug approach of the corticosteroids has been described as a fundamentally sound approach for the development of safer anti-inflammatory steroids devoid of systemic side effects. In our continued efforts under the antedrug paradigm, we have recently extended this effort to synthesize the 21-thioalkylether derivatives of methyl 16- prednisolonecarboxylates. The 21-mesylate of the methyl-16-perdnisolonecarboxylates and 9-fluoro-17-dehydro methyl 16-prednisolonecarboxylate were reacted with Na-thioalkoxides to furnish the desired thioalkylethers in 60-75% yields. These newly synthesized thioalkylether steroid series were tested for their in vitro metabolism and corticosteroid receptor binding affinity. They were metabolized in predictable manner to inactive 16-carboxylic acids. All the newly synthesized antedrugs showed lowered glucocorticoid receptor binding affinity than prednisolone indicating that the replacement of the 21-OH function with thioalkylether of the 16-prednisolone carboxylate esters decreases their receptor binding affinity.
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Cite this article as:
Khan F. M. Omar, Park K. Kwan, Glynn N. Sharye and Lee J. Henry, New Steroidal Anti-Inflammatory Antedrugs: 21-Thioalkylether Derivatives of Methyl 16-Prednisolone Carboxylates, Medicinal Chemistry 2007; 3 (6) . https://dx.doi.org/10.2174/157340607782360317
DOI https://dx.doi.org/10.2174/157340607782360317 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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