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

• Published in: Journal of medicinal chemistry 2024-12, Vol.67 (23), p.21143
• Main Authors: Ergül, Azize Gizem, Jordan, Paul M, Dahlke, Philipp, Bal, Nur Banu, Olğaç, Abdurrahman, Uludağ, Orhan, Werz, Oliver, Çalışkan, Burcu, Banoglu, Erden
• Format: Article
• Language: English
• Subjects: Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Dinoprostone - antagonists & inhibitors; Dinoprostone - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Fever - drug therapy; Guinea Pigs; Humans; Inflammation - drug therapy; Male; Microsomes - drug effects; Microsomes - metabolism; Pain - drug therapy; Prostaglandin-E Synthases - antagonists & inhibitors; Prostaglandin-E Synthases - metabolism; Structure-Activity Relationship
• ISSN: 1520-4804

Microsomal prostaglandin E 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 IC values of 0.27-7.0 nM in a cell-free assay for prostaglandin (PG)E production. Compound (AGU654) demonstrated remarkable selectivity for mPGES-1 (IC = 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 PGE production triggered by bacterial exotoxins while sparing other prostaglandins. Furthermore, 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.