Abstract
Glucocorticoids (GCs) are commonly used topical treatments for skin diseases but are associated with both local and systemic side effects. In this study, we describe a selective non-steroidal glucocorticoid receptor (GR) agonist for topical use, LEO 134310, which is rapidly deactivated in the blood resulting in low systemic exposure and a higher therapeutic index in the TPA-induced skin inflammation mouse model compared with betamethasone valerate (BMV) and clobetasol propionate (CP). Selectivity of LEO 134310 for GR was confirmed within a panel of nuclear receptors, including the mineralocorticoid receptor (MR), which has been associated with induction of skin atrophy. Topical treatment with LEO 134310 in minipigs did not result in any significant reduction in epidermal thickness in contrast to significant epidermal thinning induced by treatment with BMV and CP. Thus, the profile of LEO 134310 may potentially provide an effective and safer treatment option for skin diseases compared with currently used glucocorticoids.
Highlights
Glucocorticoids (GCs) are commonly used topical treatments for skin diseases but are associated with both local and systemic side effects
LEO 134310 is a nonsteroidal glucocorticoid receptor (GR) agonist consisting of a gamma-hydroxy-butyrolactone derivatized with a mixed aromatic/aliphatic substituent containing a central benzoate ester and two amides[15]
We have demonstrated in vitro and in vivo efficacy of LEO 134310, a novel non-steroidal GR agonist
Summary
Glucocorticoids (GCs) are commonly used topical treatments for skin diseases but are associated with both local and systemic side effects. LEO 134310 achieved full efficacy ( Emax of 100 and 95%, respectively) in transrepression and transactivation assays using HeLa reporter cell lines (Table 3). No significant activation of MR was observed in a specific reporter cell line, in contrast to the positive control aldosterone and two steroidal GR agonists, CP and BMV (Fig. 1).
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