جهت دسترسی به کاربرگه ی زیر، از این لینک استفاده کنید. http://dl.kums.ac.ir/handle/Hannan/125778
Title: Rational Development of a Potent 15-Lipoxygenase-1 Inhibitor with in Vitro and ex Vivo Anti-inflammatory Properties
Authors: Eleftheriadis, Nikolaos;Neochoritis, Constantinos G.;Leus, Niek G J;Van Der Wouden, Petra E.;D??mling, Alexander;Dekker, Frank J.
Year: 2015
Abstract: Human 15-lipoxygenase-1 (h-15-LOX-1) is a mammalian lipoxygenase and plays an important role in several inflammatory lung diseases such as asthma, COPD, and chronic bronchitis. Novel potent inhibitors of h-15-LOX-1 are required to explore the role of this enzyme further and to enable drug discovery efforts. In this study, we applied an approach in which we screened a fragment collection that is focused on a diverse substitution pattern of nitrogen-containing heterocycles such as indoles, quinolones, pyrazoles, and others. We denoted this approach substitution-oriented fragment screening (SOS) because it focuses on the identification of novel substitution patterns rather than on novel scaffolds. This approach enabled the identification of hits with good potency and clear structure-activity relationships (SAR) for h-1-5-LOX-1 inhibition. Molecular modeling enabled the rationalization of the observed SAR and supported structure-based design for further optimization to obtain inhibitor 14d that binds with a Ki of 36 nM to the enzyme. In vitro and ex vivo biological evaluations of our best inhibitor demonstrate a significant increase of interleukin-10 (IL-10) gene expression, which indicates its anti-inflammatory properties.
URI: http://dl.kums.ac.ir/handle/Hannan/125778
ISSN: 1520-4804 (Electronic)\r0022-2623 (Linking)
volume: Volume 58
Issue: Issue 19
month: October
More Information: Volume : 58Issue : 19Start page : 7850
END PAGES : 7862
Appears in Collections:Journal of Medicinal Chemistry

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