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SYNTHESIS OF STEROID 6‐CARBOXYLATE ESTERS: ANALOGS OF METHYL 11β , 17 α , 21‐TRIHYDROXY‐3, 20‐DIOXO‐PREGNA‐1, 4‐DIENE‐6‐CARBOXYLATE
Author(s) -
Gassett Sandi Rena,
Lee Henry J.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.756.5
Subject(s) - steroid , chemistry , carboxylate , in vitro , systemic circulation , anti inflammatory , pharmacology , stereochemistry , biochemistry , medicine , hormone
Systemic side effects of anti‐inflammatory steroids may be minimized by incorporation of a labile group which is metabolized to make inactive steroid acids upon entry into the systemic circulation (antedrug concept). Thus, antedrugs act locally and are devoid of systemic toxicities. Flonase® was the first clinically available steroidal thiocarbonate inhalation antedrug marketed by Glaxo SmithKline. In the continuing efforts to increase local to systemic activity ratios of potent steroidal anti‐inflammatory antedrugs, a series of anti‐inflammatory steroids with a carboxylate ester at the carbon 6 position and derivatives were synthesized. These derivatives were evaluated for anti‐inflammatory activity and the effects to bind to glucocorticoid receptors, and to inhibit nitric oxide (NO) generation in vitro . The new compounds are designed to rapidly metabolized to inactive compounds upon entry into the systemic circulation. The objective of our research is to develop a highly potent, and yet safer anti‐inflammatory steroid. These results provide a solid rational basis for the development of therapeutically useful non‐systemic corticosteroids for prolonged local use.