New steroidal anti-inflammatory antedrugs: 21-thioalkylether derivatives of methyl 16-prednisolone carboxylates.
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.
College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USA. omar.khan@famu.edu
M
M
Omar
F
F
Khan
Kwan K
KK
Park
Sharye N
SN
Glynn
Henry J
HJ
Lee
D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000378:metabolism; D011485:Protein Binding; D011987:Receptors, Steroid / Q000378:metabolism; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D002264:Carboxylic Acids; D011987:Receptors, Steroid; D011239:Prednisolone