Dataset Information

Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile.

ABSTRACT:

Background and purpose

Glucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti-inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17? position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such molecules would retain anti-inflammatory activity.

Experimental approach

The pharmacological properties of GW870086 were compared with fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling.

Key results

GW870086 repressed inflammatory cytokine release from lung epithelial cells in a similar manner to FP but antagonized the effect of dexamethasone on MMTV-driven reporter gene transactivation. GW870086 had a strong effect on the expression of some glucocorticoid-regulated genes (such as PTGS2), while having minimal impact on the expression of other known target genes (such as SGK). GW870086 retained the ability to strengthen tight junctions in epithelial cell culture but, unlike FP, was unable to protect the culture from elastase-mediated damage. In murine models of irritant-induced contact dermatitis and ovalbumin-induced allergic inflammation, GW870086 showed comparable anti-inflammatory efficacy to FP.

Conclusion and implications

GW870086 is a potent anti-inflammatory compound with a unique ability to regulate only a subset of those genes that are normally affected by classical glucocorticoids. It has the potential to become a new topical steroid with a different safety profile to existing therapies.

SUBMITTER: Uings IJ

PROVIDER: S-EPMC3831715 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile.

Uings I J IJ Needham D D Matthews J J Haase M M Austin R R Angell D D Leavens K K Holt J J Biggadike K K Farrow S N SN

British journal of pharmacology 20130701 6

<h4>Background and purpose</h4>Glucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti-inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17α position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such mo ...[more]

PMID: 23639214

Similar Datasets

Project description:BackgroundBiotransformation of organic compounds by using microbial whole cells provides an efficient approach to obtain novel analogues which are often difficult to synthesize chemically. In this manuscript, we report for the first time the microbial transformation of a synthetic anabolic steroidal drug, oxymetholone, by fungal cell cultures.ResultsIncubation of oxymetholone (1) with Macrophomina phaseolina, Aspergillus niger, Rhizopus stolonifer, and Fusarium lini produced 17?-hydroxy-2-(hydroxy-methyl)-17?-methyl-5?-androstan-1-en-3-one (2), 2?,17?-di(hydroxyl-methyl)-5?-androstan-3?,17?-diol (3), 17?-methyl-5?-androstan-2?,3?,17?-triol (4), 17?-hydroxy-2-(hydroxymethyl)-17?-methyl-androst-1,4-dien-3-one (5), 17?-hydroxy-2?-(hydroxy-methyl)-17?-methyl-5?-androstan-3-one (6), and 2?-(hydroxymethyl)-17?-methyl-5?-androstan-3?-17?-diol (7). Their structures were deduced by spectral analyses, as well as single-crystal X-ray diffraction studies. Compounds 2-5 were identified as the new metabolites of 1. The immunomodulatory, and anti-inflammatory activities and cytotoxicity of compounds 1-7 were evaluated by observing their effects on T-cell proliferation, reactive oxygen species (ROS) production, and normal cell growth in MTT assays, respectively. These compounds showed immunosuppressant effect in the T-cell proliferation assay with IC50 values between 31.2 to 2.7 ?g/mL, while the IC50 values for ROS inhibition, representing anti-inflammatory effect, were in the range of 25.6 to 2.0 ?g/mL. All the compounds were found to be non-toxic in a cell-based cytotoxicity assay.ConclusionMicrobial transformation of oxymetholone (1) provides an efficient method for structural transformation of 1. The transformed products were obtained as a result of de novo stereoselective reduction of the enone system, isomerization of double bond, insertion of double bond and hydroxylation. The transformed products, which showed significant immunosuppressant and anti-inflammatory activities, can be further studied for their potential as novel drugs.

Project description:BackgroundAlthough athletic endeavours are associated with a high amount of physical stress and injury, the prevalence of pain is underreported in the sports medicine literature with only a few studies reporting pain on collegiate athletes or exploring sex difference of pain. Impact of pain on athlete availability, training and performance can be mitigated when key epidemiological information is used to inform adequate pain management strategies. This study aims to 1) provide an epidemiological profile of self-reported pain experienced by the National Collegiate Athletic Association (NCAA) athletes by sex during the first half of the 2019 season, 2) describe their self-reported non-steroidal anti-inflammatory drug (NSAID) use.MethodsOnline survey was completed by athletes at three NCAA institutions from 1 August to 30 September 2019. Descriptive statistics were used to describe player demographic data, self-reported pain and self-reported NSAID use. Pain incidence proportion were calculated.ResultsTwo hundred thirty female athletes and 83 male athletes completed the survey. Self-reported pain incidence proportion for female athletes was 45.0 (95% CI 41.5-48.5) vs 34.9 (95% CI 29.4-40.4) for male athletes. Majority of the athletes did not report pain (55% female vs 62% male) during the first half of the 2019 season. Female athletes reported pain in their back (35%), knee (26%), and ankle/foot (23%) whilst male athletes reported pain in their knee (35%), back (28%), and shoulder (24%). Of all athletes, 28% female vs 20% male athletes reported currently taking NSAIDs. Of athletes that reported pain, 46% female vs 38% male athletes currently took NSAIDs. 70% female vs 61% male athletes self-purchased NSAIDs, and 40% female vs 55% male athletes consumed alcohol.ConclusionsHalf of female athletes and one in three male athletes reported pain. Most commonly back, knee and foot/ankle pain and knee, back and shoulder pain was reported in female and male athletes respectively. One in four female athletes and one in five male athletes use NSAIDs for pain or prophylactic purpose. Majority self-purchase these medications indicating need for health literacy interventions to mitigate potential adverse effects.

Dataset Information

Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets