Novel Benzimidazole\nDerivatives as Potent Inhibitors\nof Microsomal Prostaglandin E<sub>2</sub> Synthase 1 for the Potential\nTreatment of Inflammation, Pain, and Fever

Microsomal prostaglandin E<sub>2</sub> synthase 1 (mPGES-1)\nis\na promising target for treating inflammatory diseases and pain. This\nstudy introduces a novel series of benzimidazoles, with the most potent\nanalogs exhibiting IC<sub>50</sub> values of 0.27–7.0 nM in\na cell-free assay for prostaglandin (PG)E<sub>2</sub> production.\nCompound <b>44</b> (AGU654) demonstrated remarkable selectivity\nfor mPGES-1 (IC<sub>50</sub> = 2.9 nM) over COX-1, COX-2, 5-LOX, and\nFLAP, along with excellent bioavailability. Metabololipidomics analysis\nwith activated human monocyte-derived macrophages and human whole\nblood revealed that AGU654 selectively suppresses PGE<sub>2</sub> production\ntriggered by bacterial exotoxins while sparing other prostaglandins.\nFurthermore, <i>in vivo</i> studies showed that AGU654 significantly\nalleviated fever, inflammation, and inflammatory pain in preclinical\nguinea pig models, suggesting that it could be an effective strategy\nfor managing inflammatory diseases. In conclusion, these benzimidazole\nderivatives warrant further exploration into new and alternative analogs,\npotentially uncovering novel compounds with a favorable pharmacological\nprofile possessing significant anti-inflammatory and analgesic properties.