Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones

European Journal of Medicinal Chemistry
Perihan A ElzahharAhmed S F Belal

Abstract

In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARγ ligands. Challenging our design with pre-synthetic docking experiments on PPARγ showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARγ agonist, potent COX-2 antagonist (nanomolar IC50 values) and moderate 15-LOX inhibitor (micromolar IC50 values). We envisioned such outcome as a prototypical balanced modulation of the 3 inflammatory targets. In vitro glucose uptake assay defined six compounds as insulin-sensitive and the other two as insulin-independent glucose uptake enhancers. Also, they were able to induce PPARγ nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhibition of monocyte to macrophage differentiation, suppression of LPS-induced inflammatory cytokine production in macrophages, as well as significant in vivo anti-inflammatory activity. Ligand co-crystallized PPARγ X-ray of one of MTDLs has identified...Continue Reading

Citations

Nov 27, 2019·Pharmacology Research & Perspectives·Michael J Parnham, Gerd Geisslinger
Feb 5, 2021·European Journal of Medicinal Chemistry·Mengwu XiaoAixi Hu
Dec 8, 2020·Frontiers in Cardiovascular Medicine·Ibrahim AlZaimAhmed F El-Yazbi
Feb 24, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Perihan A ElzahharAhmed F El-Yazbi
Aug 3, 2021·The Journal of Biological Chemistry·Rebecca L FrkicJohn B Bruning

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