Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties

• Combination of substitution oriented screening (SOS) and MCR enables identification of novel 15-LOX-1 inhibitors.
• ThioLox has very favorable ligand efficiency metric and physicochemical properties.
• ThioLox inhibits pro-inflammatory gene expression in ex vivo biological evaluation in precision-cut lung slices (PCLS).
• ThioLox acts protective against glutamate toxicity in in vitro studies on neuronal HT-22 cells.

The enzyme 15-lipoxygenase-1 (15-LOX-1) plays a dual role in diseases with an inflammatory component. On one hand 15-LOX-1 plays a role in pro-inflammatory gene expression and on the other hand it has been shown to be involved in central nervous system (CNS) disorders by its ability to mediate oxidative stress and damage of mitochondrial membranes under hypoxic conditions. In order to further explore applications in the CNS, novel 15-LOX-1 inhibitors with favorable physicochemical properties need to be developed. Here, we present Substitution Oriented Screening (SOS) in combination with Multi Component Chemistry (MCR) as an effective strategy to identify a diversely substituted small heterocyclic inhibitors for 15-LOX-1, denoted ThioLox, with physicochemical properties superior to previously identified inhibitors. Ex vivo biological evaluation in precision-cut lung slices (PCLS) showed inhibition of pro-inflammatory gene expression and in vitro studies on neuronal HT-22 cells showed a strong protection against glutamate toxicity for this 15-LOX-1 inhibitor. This provides a novel approach to identify novel small with favorable physicochemical properties for exploring 15-LOX-1 as a drug target in inflammatory diseases and neurodegeneration.

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