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

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 17α 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 {"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}GW870086 were compared with fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling.

Key Results

{"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}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. {"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}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). {"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}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, {"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}GW870086 showed comparable anti-inflammatory efficacy to FP.

Conclusion and Implications

{"type":"entrez-nucleotide","attrs":{"text":"GW870086","term_id":"295652431","term_text":"GW870086"}}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.