New Steroidal Anti-Inflammatory Antedrugs: 21-Thioalkylether Derivatives of Methyl 16-Prednisolone Carboxylates

M. Omar   F.   Khan; Kwan   K.   Park; Sharye   N.   Glynn; Henry   J.   Lee

doi:10.2174/157340607782360317

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

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