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Ballerup, Denmark

Costantini V.J.A.,Aptuit S.r.l. | Corsi M.,Aptuit S.r.l. | Dunstl G.,Front End Innovation | Bettelini L.,Aptuit S.r.l. | And 2 more authors.
Experimental Dermatology

Experiments were conducted to develop a model to study the effect of oral and topical administration of the NK1 receptor antagonist aprepitant, on scratching behaviour in gerbils. The gerbil was selected due to its relevance for human NK1 receptor pharmacology. Intradermal injection of a specific NK1 receptor agonist GR73632 (100 nmol/100 μl) at the rostral back of gerbils produced scratching of the injection site. This could be attenuated by intradermal co-administration of a selective NK1 receptor antagonist aprepitant (30-100-300 nmol), demonstrating the role of dermal NK1 receptor in elicitation of scratching behaviour. Likewise, scratching was attenuated by oral (0.3-3-30 mg/kg) or topical application (0.01-0.1-1% w/v) of aprepitant and pharmacokinetic analysis of aprepitant levels in brain, blood and skin supported that efficacy of topically applied aprepitant was due to dermal rather than central target engagement. In conclusion, we showed that NK1 agonist-induced scratching in the gerbil can be reversed by systemic and topical administration of aprepitant. This test system may provide a useful model for the in vivo assessment of putative antipruritic agents. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source

Renata H.,Scripps Research Institute | Zhou Q.,Scripps Research Institute | Dunstl G.,Front End Innovation | Felding J.,Front End Innovation | And 3 more authors.
Journal of the American Chemical Society

The natural product ouabagenin is a complex cardiotonic steroid with a highly oxygenated skeleton. This full account describes the development of a concise synthesis of ouabagenin, including the evolution of synthetic strategy to access hydroxylation at the C19 position of a steroid skeleton. In addition, approaches to install the requisite butenolide moiety at the C17 position are discussed. Lastly, methodology developed in this synthesis has been applied in the generation of novel analogues of corticosteroid drugs bearing a hydroxyl group at the C19 position.(Chemical Equation Presented). © 2015 American Chemical Society. Source

Jin Y.,Scripps Research Institute | Yeh C.-H.,Scripps Research Institute | Kuttruff C.A.,Scripps Research Institute | Jorgensen L.,Scripps Research Institute | And 4 more authors.
Angewandte Chemie - International Edition

Ingenol derivatives with varying degrees of oxidation were prepared by two-phase terpene synthesis. This strategy has allowed access to analogues that cannot be prepared by semisynthesis from natural ingenol. Complex ingenanes resulting from divergent C-H oxidation of a common intermediate were found to interact with protein kinase C in a manner that correlates well with the oxidation state of the ingenane core. Even though previous work on ingenanes has suggested a strong correlation between potential to activate PKCδ and induction of neutrophil oxidative burst, the current study shows that the potential to activate PKCβII is of key importance while interaction with PKCδ is dispensable. Thus, key modifications of the ingenane core allowed PKC isoform selectivity wherein PKCδ-driven activation of keratinocytes is strongly reduced or even absent while PKCβII-driven activation of neutrophils is retained. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

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