Rational Development of a Potent 15-Lipoxygenase-1 Inhibitor with in Vitro and ex Vivo Anti-inflammatory Properties.
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 14 d 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.
Department of Pharmaceutical Gene Modulation, ‡Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen , Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Nikolaos
N
Eleftheriadis
Department of Pharmaceutical Gene Modulation, ‡Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen , Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Constantinos G
CG
Neochoritis
Department of Pharmaceutical Gene Modulation, ‡Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen , Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Niek G J
NG
Leus
Department of Pharmaceutical Gene Modulation, ‡Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen , Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Petra E
PE
van der Wouden
Department of Pharmaceutical Gene Modulation, ‡Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen , Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Alexander
A
Dömling
Department of Pharmaceutical Gene Modulation, ‡Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen , Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Frank J
FJ
Dekker
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016859:Lipoxygenase Inhibitors; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase