Novel thiazolones for the simultaneous modulation of PPARγ, COX-2 and 15-LOX to address metabolic disease-associated portal inflammation
<p dir="ltr">A hybrid pharmacophore model, based on structural motifs previously identified by our team, was employed to generate ligands that simultaneously target COX-2, 15-LOX, and PPARγ in the context of metabolic dysfunction-associated fatty liver disease (MAFLD). Notable COX-2...
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2025
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| Summary: | <p dir="ltr">A hybrid pharmacophore model, based on structural motifs previously identified by our team, was employed to generate ligands that simultaneously target COX-2, 15-LOX, and PPARγ in the context of metabolic dysfunction-associated fatty liver disease (MAFLD). Notable COX-2 inhibitory activities (IC<sub>50</sub> = 0.065–0.24 μM) were observed relative to celecoxib (IC<sub>50</sub> = 0.049 μM). The two most effective 15-LOX inhibitors, <b>2a</b> and <b>2b</b>, exhibited 69 % and 57% of quercetin's action, respectively. Utilizing the rat hemi-diaphragm model to assess <i>in vitro</i> glucose uptake capacity, compounds <b>2a</b> and <b>2b</b> demonstrated significant glucose uptake potential in the absence of insulin, surpassing that of pioglitazone. Compound 2a activated PPARγ with an EC<sub>50</sub> value of 3.4 μM in a Gal4-hybrid reporter gene assay, indicating partial agonistic action. Interesting binding interactions with targets of interest were identified by molecular docking studies. As well, the expression levels of 20-HETE, Il-1β and TNF-α were decreased in LPS-challenged RAW264.7 macrophages upon treatment with compound <b>2a</b>. The pharmacokinetic analysis of <b>2a</b> and assessment of its in vivo efficacy in addressing hepatic impairment in rat models of diabetes and pre-diabetes were carried out. Together, these findings may offer preliminary insights into the potential of these compounds for further refinement in the existing therapeutic arsenals for metabolic diseases.</p><h2>Other Information</h2><p dir="ltr">Published in: European Journal of Medicinal Chemistry<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.ejmech.2025.117415" target="_blank">https://dx.doi.org/10.1016/j.ejmech.2025.117415</a></p> |
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