title: In vitro anti-inflammatory activities of new steroidal antedrugs: [16alpha,17alpha-d] Isoxazoline and [16alpha,17alpha-d]-3'-hydroxy-iminoformyl isoxazoline derivatives of prednisolone and 9alpha-fluoroprednisolone.
abstract: A series of new anti-inflammatory steroidal antedrugs with C-16,17-isoxazoline ring system were synthesized and their pharmacological activities were evaluated. We reported earlier that these compounds are promising antedrugs based on the results of 5-day rat croton oil ear edema assay. In the present study, most of these compounds showed high binding affinities to the glucocorticoid receptor of liver cytosol. 21-acetyloxy-9alpha-fluoro-11beta-hydroxy-3,20-dioxo-1,4-pregnadieno [16alpha,17alpha-d] isoxazoline (FP-ISO-21AC) and 11beta,21-dihydroxy-9alpha-fluoro-3,20-dioxo-1,4-pregnadieno [16alpha,17alpha-d] isoxazoline (FP-ISO-21OH) were found 5.0-, 5.3-fold more potent than prednisolone, respectively. Inhibitory effects of the antedrugs on the nitric oxide (NO) production were assessed using LPS-stimulated RAW 264.7 murine macrophage cells. All these steroidal antedrugs exhibited concentration-dependent inhibition of NO production, but their relative potencies were lower than prednisolone. In vitro metabolism study in rat plasma showed that FP-ISO-21AC and 21-acetyloxy-9alpha-fluoro-11beta-hydroxy-3,20-dioxo-1,4-pregnadieno [16alpha,17alpha-d]-3'-hydroxyiminoformyl isoxazoline (FP-OXIM-21AC) were hydrolyzed rapidly, with the half-lives of 2.1 and 4.2 min, respectively. The half-lives of FP-ISO-21OH and 11beta,21-dihydroxy-9alpha-fluoro-3,20-dioxo-1,4-pregnadieno [16alpha,17alpha-d]-3'-hydroxyiminoformyl isoxazoline (FP-OXIM-21OH) were 92.2 and 110.2 min, respectively.
authors.affiliation: Center for Anti-Inflammatory Research, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, FL 32307, USA. kwankyun.park@famu.edu
authors.forename: Kwan-K
authors.initials: KK
authors.lastname: Park
authors.forename: Dong-H
authors.initials: DH
authors.lastname: Ko
authors.forename: Z
authors.initials: Z
authors.lastname: You
authors.forename: M Omar F
authors.initials: MO
authors.lastname: Khan
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004427:Ear Diseases / Q000139:chemically induced / Q000188:drug therapy; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011246:Pregnadienetriols; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D007555:Isoxazoles; D008070:Lipopolysaccharides; D011246:Pregnadienetriols; D011965:Receptors, Glucocorticoid; D009569:Nitric Oxide; D011239:Prednisolone