New steroidal anti-inflammatory antedrugs: methyl 21-desoxy-21-chloro-11beta,17alpha-dihydroxy-3,20-dioxo-1, 4-pregnadiene-16alpha-carboxylate, methyl 21-desoxy-21-chloro-11beta-hydroxy-3,20-dioxo-1, 4-pregnadiene-16alpha-carboxylate, and their 9alpha-fluoro derivatives*.

Abstract

To a series of 21-desoxy-21-chloro-corticosteroids, a metabolically labile methoxycarbonyl group at C-16 has been incorporated. The approach is to synthesize locally active compounds that are hydrolyzed to inactive and readily excretable acid metabolites upon entry into the systemic circulation. Novel antedrugs were evaluated for anti-inflammatory activity and their adverse effects in an acute and semichronic croton oil-induced ear edema bioassay. Binding affinity to glucocorticoid receptors and induction of L-tyrosine-2-oxoglutarate aminotransferase were studied in hepatoma tissue culture cells. After a single topical application in the croton oil-induced ear edema bioassay, treatment with all the compounds resulted in dose-dependent inhibition of edema. From these dose-response profiles, the following ID(50) values (nmol/ear resulting in a 50% reduction of edema) were calculated: 540, 618, 454, and 346 nmol for prednisolone (P), methyl 21-desoxy-21-chloro-11beta,17alpha-dihydroxy-3,20-dioxo-1, 4-pregnadien-16alpha-carboxylate (PClCM), methyl 21-desoxy-21-chloro-11beta,17alpha-dihydroxy-9alpha-fl uoro-3, 20-dioxo-1,4-pregnadien-16alpha-carboxylate (FPClCM), and methyl 21-desoxy-21-chloro-9alpha-fluoro-11beta-hydroxy-3,20-dioxo- 1, 4-pregnadien-16alpha-carboxylate (FDPClCM), respectively. Results of the 5-day rat croton oil ear edema bioassay indicated that, in contrast with the parent compound P, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights, or plasma corticosterone levels. The binding affinities for cytosolic hepatoma tissue culture glucocorticoid receptors were 33, 201, 471, 5304, and 3765 nM for P, PClCM, FPClCM, methyl 21-desoxy-21-chloro-11beta-hydroxy-3,20-dioxo-1, 4-pregnadien-16alpha-carboxylate (DPClCM), and FDPClCM, respectively. Collectively, results of these investigations suggest that modifications of P, which included replacement of 21-hydroxyl group with chlorine and addition of 16-methoxycarbonyl group with or without 17-hydroxyl moiety, retained the topical anti-inflammatory activity of the parent compound P without significant adverse systemic effects.

• Authors: D Ko, A S Heiman, M Chen, H J Lee
• Journal: Steroids (Steroids) Vol. 65 Issue 4 Pg. 210-8 (Apr 2000) ISSN: 0039-128X [Print] United States
• PMID: 10713309 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents
• Pregnadienes
• Receptors, Glucocorticoid
• methyl 21-desoxy-21-chloro-11,17-dihydroxy-3,20-dioxo-1,4-pregnadiene-16-carboxylate
• methyl 21-desoxy-21-chloro-11-hydroxy-3,20-dioxo-1,4-pregnadiene-16-carboxylate
• Croton Oil
• Prednisolone
• Tyrosine Transaminase

Topics

• Animals
• Anti-Inflammatory Agents (chemistry, metabolism, pharmacology)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Croton Oil
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Ear Diseases (chemically induced, drug therapy)
• Edema (chemically induced, drug therapy)
• Male
• Prednisolone (metabolism, pharmacology)
• Pregnadienes (chemistry, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Glucocorticoid (metabolism)
• Tumor Cells, Cultured
• Tyrosine Transaminase (drug effects, metabolism)