title: Synthesis and pharmacological evaluations of new steroidal anti-inflammatory antedrugs: 9alpha-Fluoro-11beta,17alpha,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16alpha-carboxylate (FP16CM) and its derivatives.
abstract: In continuing efforts to develop potent anti-inflammatory steroids without systemic adverse effects, methyl 9alpha-fluoro-11beta,17alpha,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16alpha-carboxylate (FP16CM) and its 16-alkoxycarbonyl derivatives (FP16CE, FP16CP and FP16CB) were synthesized based on the antedrug concept. The steroids were evaluated for their pharmacological activities and adverse systemic effects. All steroidal antedrugs showed both binding affinity to the glucocorticoid receptor in liver cytosol and inhibitory effect on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophage cell. These compounds also inhibited croton-oil-induced ear edema and showed no systemic effects such as thymus atrophy and suppression of corticosterone level after 5-day treatment. Among those compounds tested, FP16CM showed the highest activities in receptor binding, NO inhibition and ear edema, these activities were comparable to those of prednisolone. Hydrolysis study in plasma showed that FP16CB was hydrolyzed rapidly, with the half-live (T1/2) of 3.2 min and the half-lives of other compounds were between 16.9 and 29.4 min. These results support the antedrug concept, of which the decrease in systemic adverse effects is attributed to fast hydrolysis to inactive metabolite in the systemic circulation.
authors.affiliation: Center for Anti-Inflammatory Research, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee FL 32307, USA. kwankyun.park@famu.edu
authors.forename: Kwan-Kyun
authors.initials: KK
authors.lastname: Park
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Ko
authors.forename: Zhengqing
authors.initials: Z
authors.lastname: You
authors.forename: Ann S
authors.initials: AS
authors.lastname: Heiman
authors.forename: Henry Joung
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D004427:Ear Diseases / Q000188:drug therapy; D004487:Edema / Q000188:drug therapy; D004951:Esterification; D006868:Hydrolysis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D011246:Pregnadienetriols / Q000138:chemical synthesis* / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D011246:Pregnadienetriols; D011965:Receptors, Glucocorticoid; C107434:methyl 3,20-dioxo-9-fluoro-11,17,21-trihydroxy-1,4-pregnadiene-16-carboxylate; D009569:Nitric Oxide