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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.
Highlights
With an aging population, UV-mediated skin damage and skin aging-related diseases represent an increasing problem and there is an increasing demand for novel therapies against skin diseases [1]
11β-HSD1 inhibitors for skin applications cross-coupling step, it is indifferent which aromatic partner is employed as an aryl bromide and which as an aryl boronic acid: as a result, four alternative synthesis strategies are possible for each library compound (Fig 2)
All four synthesis routes gave satisfactory results in terms of yields, but strategy B was less practical than the remaining approaches, due to the need for chromatographic purification after amide formation, whereas the alternative routes generally allow to obtain the product in pure form after simple extractive work-up
Summary
UV-mediated skin damage and skin aging-related diseases represent an increasing problem and there is an increasing demand for novel therapies against skin diseases [1]. Excessive exposure to UV light results in skin damage, with erythema and DNA damage, oxidative stress, and an inflammatory response with the production of pro-inflammatory mediators such as tumor necrosis factor α (TNFα), interleukin 6 (IL6) and interleukin 1β (IL1β), and the activation of nuclear factor-κB (NF-κB) [2,3,4]. 11β-HSD1 inhibitors for skin applications 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
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