Characterization of a novel non-steroidal glucocorticoid receptor agonist optimized for topical treatment

被引：10

作者：

Eirefelt, Stefan ^{[1
]}

Stahlhut, Martin ^{[1
]}

Svitacheva, Naila ^{[1
]}

Carnerup, Martin A. ^{[1
]}

Da Rosa, Joel Mauricio Correa ^{[1
]}

Ewald, David Adrian ^{[1
]}

Marstrand, Troels T. ^{[1
]}

Krogh-Madsen, Mikkel ^{[1
]}

Dunstl, Georg ^{[1
]}

Dack, Kevin Neil ^{[1
]}

Ollerstam, Anna ^{[1
]}

Norsgaard, Hanne ^{[1
]}

机构：

[1] LEO Pharma AS, Ind Pk 55, Ballerup, Denmark

来源：

SCIENTIFIC REPORTS | 2022年 / 12卷 / 01期

关键词：

MINERALOCORTICOID RECEPTOR; EPIDERMAL ATROPHY; CLINICAL-EFFICACY; PHARMACOKINETICS; SKIN; REMIFENTANIL; CLEVIDIPINE; ANTAGONIST; METABOLITE; DOLASETRON;

D O I：

10.1038/s41598-022-05471-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

共 41 条

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