Novel 1,3,4-oxadiazole derivatives as highly potent microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors

Tuğçe Gür Maz; Philipp Dahlke; Azize Gizem Ergül; Abdurrahman Olğaç; Paul M Jordan; Burcu Çalışkan; Oliver Werz; Erden Banoglu

doi:10.1016/j.bioorg.2024.107383

Novel 1,3,4-oxadiazole derivatives as highly potent microsomal prostaglandin E₂ synthase-1 (mPGES-1) inhibitors

Bioorg Chem. 2024 Apr 16:147:107383. doi: 10.1016/j.bioorg.2024.107383. Online ahead of print.

Authors

Tuğçe Gür Maz¹, Philipp Dahlke², Azize Gizem Ergül¹, Abdurrahman Olğaç¹, Paul M Jordan³, Burcu Çalışkan¹, Oliver Werz³, Erden Banoglu⁴

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Taç Sok. No:3 Yenimahalle 06560 Ankara, Turkey.
² Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-7743 Jena, Germany.
³ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-7743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, D-07743 Jena, Germany.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Taç Sok. No:3 Yenimahalle 06560 Ankara, Turkey. Electronic address: banoglu@gazi.edu.tr.

PMID: 38653151
DOI: 10.1016/j.bioorg.2024.107383

Abstract

Selective inhibition of microsomal prostaglandin E₂ synthase-1 (mPGES-1) is implicated as a new therapeutic modality for the development of new-generation anti-inflammatory drugs. Here, we present the discovery of new and potent inhibitors of human mPGES-1, i.e., compounds 13, 15-25, 29-30 with IC₅₀ values in the range of 5.6-82.3 nM in a cell-free assay of prostaglandin (PG)E₂ formation. We also demonstrate that 20 (TG554, IC₅₀ = 5.6 nM) suppresses leukotriene (LT) biosynthesis at low µM concentrations, providing a benchmark compound that dually intervenes with inflammatory PGE₂ and LT biosynthesis. Comprehensive lipid mediator (LM) metabololipidomics with activated human monocyte-derived macrophages showed that TG554 selectively inhibits inflammatory PGE₂ formation over all cyclooxygenase (COX)-derived prostanoids, does not cause substrate shunting towards 5-lipoxygenase (5-LOX) pathway, and does not interfere with the biosynthesis of the specialized pro-resolving mediators as observed with COX inhibitors, providing a new chemotype for effective and safer anti-inflammatory drug development.

Keywords: Arachidonic acid; Benzyloxyphenyl; Cyclooxygenase; Leukotrienes; Lipidomics.