Linked Life Data

9185298

Source:http://linkedlifedata.com/resource/pubmed/id/9185298

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
1997-8-28
pubmed:abstractText
Focused efforts have been made to increase local-to-systemic activity ratios of potent anti-inflammatory steroids for local and/or topical applications. The approach taken in the present investigation is based upon the concept of "antedrug," defined as a locally active compound that exerts its action at the application site but rapidly undergoes a predictable biotransformation to an inactive metabolite that is readily excreted upon entry into the systemic circulation. In continuing efforts to synthesize potent, anti-inflammatory steroids without systemic glucocorticoid activities, 9 alpha-fluoro-methyl 11 beta, 17 alpha, 21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate (FP16CM) and its 21-acetate derivative (FP16CMAc) have been synthesized and screened. Novel antedrugs were evaluated for antiinflammatory activity in the acute croton oil-induced ear edema bioassay, adverse systemic effects in the 5-day croton oil model, receptor binding, and concomitant L-tyrosine-2-oxoglutarate aminotransferase (EC 2.6.1.5) (TAT) enzyme induction in HTC cells in culture. Following a single topical application in the croton oil-induced ear edema bioassay, treatment with all compounds resulted in dose-dependent inhibition of edema. From these dose-response profiles, the following ID50 values (nmol resulting in a 50% reduction of edema) were calculated: 817, 540, 266, and 67 for hydrocortisone (HC), prednisolone (P), FP16CM, and FP16CMAc, respectively. Calculated relative potencies, setting HC = 1.0, were P, 1.5; FP16CM, 3.1, and FP16CMAc, 12.2. Results of the 5-day rat croton oil ear edema bioassay indicated that, in contrast to the parent compound P, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights, or plasma corticosterone levels. Relative binding potencies for cytosolic HTC glucocorticoid receptors were 1.0, 20.1, 5.4, and 2.5 for HC, P, FP16CM, and FP16CMAc, respectively. As predicted by the antedrug concept, FP16CM and FP16CMAc were very weak agonists for induction of TAT in HTC cells. Collectively, results of these investigations suggest that modification of P, which included addition of the 9-fluoro and 16-methoxycarbonyl group alone or in conjunction with a 21-acetoxy moiety, increase topical anti-inflammatory activity without significant adverse systemic effects. These new antedrugs may be useful as anti-inflammatory steroids for local applications.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0039-128X
pubmed:author
pubmed:issnType
Print
pubmed:volume
62
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
491-9
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1997
pubmed:articleTitle
New steroidal anti-inflammatory antedrugs: methyl 3,20-dioxo-9 alpha-fluoro-11 beta,17 alpha,21-trihydroxy-1,4-pregnadiene-16 alpha-carboxylate and methyl 21-acetyloxy-3,20-dioxo-11 beta, 17 alpha-dihydroxy-9 alpha-fluoro-1,4-pregnadiene-16 alpha-carboxylate.
pubmed:affiliation
Center for Anti-Inflammatory Research, Florida A & M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee 32307, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.