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PLoS One ; 12(2): e0171079, 2017.
Article in English | MEDLINE | ID: mdl-28152550

ABSTRACT

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


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Collagen/metabolism , Hydrocortisone/metabolism , Keratinocytes/drug effects , Keratinocytes/metabolism , Skin/drug effects , Skin/metabolism , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Cortisone/adverse effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , HEK293 Cells , Humans , In Vitro Techniques , Skin/radiation effects , Skin Aging/drug effects , Skin Aging/physiology , Skin Aging/radiation effects , Ultraviolet Rays/adverse effects
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