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Novel 11β-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Boudon S M, Vuorinen A, Geotti-Bianchini P, Wandeler E, Kratschmar D V, Heidl M, Campiche R, Jackson E, Odermatt A,
Project Impact of the NADPH pool in the endoplasmic reticulum on metabolic and hormonal regulation
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Original article (peer-reviewed)

Journal Plos One
Volume (Issue) 12
Page(s) e0171079
Title of proceedings Plos One
DOI 10.1371/journal.pone.0171079

Open Access

URL http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171079
Type of Open Access Publisher (Gold Open Access)

Abstract

Activity and selectivity assessment of new bi-aryl amide 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11β-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11β-HSD1 over 11β-HSD2, 17β-HSD1 and 17β-HSD2. These inhibitors also potently inhibited 11β-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11β-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11β-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging.
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