jm5b01121_si_001.pdf (2.83 MB)
Rational Development of a Potent 15-Lipoxygenase‑1 Inhibitor with in Vitro and ex Vivo Anti-inflammatory Properties
journal contribution
posted on 2015-10-08, 00:00 authored by Nikolaos Eleftheriadis, Constantinos G. Neochoritis, Niek G. J. Leus, Petra E. van der
Wouden, Alexander Dömling, Frank J. DekkerHuman
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.