Novel 11[beta]-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

• Published in: PloS one Vol. 12; no. 2; p. e0171079
• Main Authors: Boudon, Stéphanie M, Vuorinen, Anna, Geotti-Bianchini, Piero, Wandeler, Eliane, Kratschmar, Denise V, Heidl, Marc, Campiche, Remo, Jackson, Eileen, Odermatt, Alex
• Format: Journal Article
• Language: English
• Published: Public Library of Science 02.02.2017
• Subjects: Collagen; Health aspects; Hydrocortisone; Keratinocytes; Skin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0171079

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