Topical corticosteroids are widely used efficacious drugs but are associated with both local and systemic adverse effects. With the aim to provide an effective but safer topical treatment, we here describe a novel non-steroidal glucocorticoid receptor (GR) agonist with low systemic exposure and reduced potential for skin atrophy induction. 
LEO 134310 was shown to be a full GR agonist with high affinity for GR and low nanomolar potency in an inflammatory functional assay in human PBMCs. GR was the only nuclear hormone receptor affected by LEO 134310 in a panel of nuclear receptors, including the mineralocorticoid receptor, a receptor which has been associated with induction of skin atrophy. 
In blood and liver LEO 134310 is rapidly inactivated at a labile site, leading to high systemic clearance. In accordance with this profile, topical treatment with LEO 134310 in a TPA-induced dermatitis mouse model resulted in comparable efficacy to betamethasone valerate (BMV), with no systemic adverse events at maximally effective doses. In contrast, BMV and clobetasol propionate (CP) markedly reduced body weight at maximally effective doses after topical treatment. 
Furthermore, skin atrophy after 4-week application to minipigs was minimal after treatment with LEO 134310 compared with significant skin atrophy induced by treatment with CP and BMV. LEO 134310 showed similar levels of target engagement as BMV, measured by FKBP5 mRNA, but lower than CP.
Finally, topical treatment with LEO 134310 in a human skin explant model resulted in full agonism, measured by GR target engagement, albeit at higher dosage strength than required for BMV and CP.
In conclusion, LEO 134310A shows an improved therapeutic index in preclinical studies compared to traditional corticosteroids and may potentially offer an improved topical treatment solution for patients with atopic dermatitis and psoriasis.

Preclinical evaluation of a novel non-steroidal glucocorticoid receptor agonist with low systemic exposure and reduced potential for skin atrophy