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Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.
Several lines of evidence suggest the ligand-sensing transcription factor Nurr1 as a promising target to treat neurodegenerative diseases. Nurr1 modulators to validate and exploit this therapeutic potential are rare, however. To identify novel Nurr1 agonist chemotypes, we have employed the Nurr1 activator amodiaquine as template for microscale analogue library synthesis. The first set of analogues was based on the 7-chloroquiolin-4-amine core fragment of amodiaquine and revealed superior N-substituents compared to diethylaminomethylphenol contained in the template. A second library of analogues was subsequently prepared to replace the chloroquinolineamine scaffold. The two sets of analogues enabled a full scaffold hop from amodiaquine to a novel Nurr1 agonist sharing no structural features with the lead but comprising superior potency on Nurr1. Additionally, pharmacophore modeling based on the entire set of active and inactive analogues suggested key features for Nurr1 agonists.
Druggability Evaluation of the Neuron Derived Orphan Receptor (NOR-1) Reveals Inverse NOR-1 Agonists
(2022)
The neuron derived orphan receptor (NOR-1, NR4A3) is among the least studied nuclear receptors. Its physiological role and therapeutic potential remain widely elusive which is in part due to the lack of chemical tools that can directly modulate NOR-1 activity. To probe the possibility of pharmacological NOR-1 modulation, we have tested a drug fragment library for NOR-1 activation and repression. Despite low hit-rate (<1 %), we have obtained three NOR-1 ligand chemotypes one of which could be rapidly expanded to an analogue comprising low micromolar inverse NOR-1 agonist potency and altering NOR-1 regulated gene expression in a cellular setting. It confirms druggability of the transcription factor and may serve as an early tool to assess the role and potential of NOR-1.