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.
MeSH terms
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
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Amides / chemical synthesis
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Amides / chemistry
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Amides / pharmacology
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Collagen / metabolism*
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Cortisone / adverse effects
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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HEK293 Cells
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Humans
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Hydrocortisone / metabolism*
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In Vitro Techniques
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Keratinocytes / drug effects*
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Keratinocytes / metabolism*
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Skin / drug effects*
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Skin / metabolism*
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Skin / radiation effects
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Skin Aging / drug effects
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Skin Aging / physiology
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Skin Aging / radiation effects
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Ultraviolet Rays / adverse effects
Substances
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Amides
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Enzyme Inhibitors
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Collagen
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11-beta-Hydroxysteroid Dehydrogenase Type 1
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HSD11B1 protein, human
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Cortisone
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Hydrocortisone
Grants and funding
This study was supported by the Swiss National Science Foundation (
www.snf.ch) grant number 31003A-159454 to AO (AO, AV, DVK), and by DSM Nutritional Products Ltd (SB, PGB, EW, MH, RC, EJ). The Swiss National Science Foundation provided support in the form of finances for consumables for AO, AV, DVK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. DSM Nutritional Products Ltd provided support in the form of salaries for authors [SB, PGB, EW, MH, RC, EJ], and was involved in the decision of the study design and the selection of compounds to be synthesized, but did not have any additional role in the data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.