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.
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.
DSM Nutritional Products Ltd., Kaiseraugst, Switzerland.
Stéphanie M
SM
Boudon
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Anna
A
Vuorinen
DSM Nutritional Products Ltd., Kaiseraugst, Switzerland.
Piero
P
Geotti-Bianchini
DSM Nutritional Products Ltd., Kaiseraugst, Switzerland.
Eliane
E
Wandeler
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Denise V
DV
Kratschmar
DSM Nutritional Products Ltd., Kaiseraugst, Switzerland.
Marc
M
Heidl
DSM Nutritional Products Ltd., Kaiseraugst, Switzerland.
Remo
R
Campiche
DSM Nutritional Products Ltd., Kaiseraugst, Switzerland.
Eileen
E
Jackson
Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Alex
http://orcid.org/0000-0002-6820-2712
A
Odermatt
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism*; D003348:Cortisone / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism* / Q000528:radiation effects; D015595:Skin Aging / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects
D000577:Amides; D004791:Enzyme Inhibitors; D003094:Collagen; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D003348:Cortisone; D006854:Hydrocortisone