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

Ergul A. G., Jordan P. M., Dahlke P., BAL N. B., OLĞAÇ A., Uludag O., ...Daha Fazla

JOURNAL OF MEDICINAL CHEMISTRY, 2024 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1021/acs.jmedchem.4c01883
  • Dergi Adı: JOURNAL OF MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, Veterinary Science Database
  • Gazi Üniversitesi Adresli: Evet

Özet

Microsomal prostaglandin E2 synthase 1 (mPGES-1) is a promising target for treating inflammatory diseases and pain. This study introduces a novel series of benzimidazoles, with the most potent analogs exhibiting IC50 values of 0.27-7.0 nM in a cell-free assay for prostaglandin (PG)E2 production. Compound 44 (AGU654) demonstrated remarkable selectivity for mPGES-1 (IC50 = 2.9 nM) over COX-1, COX-2, 5-LOX, and FLAP, along with excellent bioavailability. Metabololipidomics analysis with activated human monocyte-derived macrophages and human whole blood revealed that AGU654 selectively suppresses PGE2 production triggered by bacterial exotoxins while sparing other prostaglandins. Furthermore, in vivo studies showed that AGU654 significantly alleviated fever, inflammation, and inflammatory pain in preclinical guinea pig models, suggesting that it could be an effective strategy for managing inflammatory diseases. In conclusion, these benzimidazole derivatives warrant further exploration into new and alternative analogs, potentially uncovering novel compounds with a favorable pharmacological profile possessing significant anti-inflammatory and analgesic properties.