Microsomal prostaglandin E2 synthase-1 and its inhibitors: Molecular mechanisms and therapeutic significance

Abstract

Inflammation is closely linked to the abnormal phospholipid metabolism chain of cyclooxygenase-2/microsomal prostaglandin E₂ synthase-1/prostaglandin E₂ (COX-2/mPGES-1/PGE₂). In clinical practice, non-steroidal anti-inflammatory drugs (NSAIDs) as upstream COX-2 enzyme activity inhibitors are widely used to block COX-2 cascade to relieve inflammatory response. However, NSAIDs could also cause cardiovascular and gastrointestinal side effects due to its inhibition on other prostaglandins generation. To avoid this, targeting downstream mPGES-1 instead of upstream COX is preferable to selectively block overexpressed PGE₂ in inflammatory diseases. Some mPGES-1 inhibitor candidates including synthetic compounds, natural products and existing anti-inflammatory drugs have been proved to be effective in in vitro experiments. After 20 years of in-depth research on mPGES-1 and its inhibitors, ISC 27864 have completed phase II clinical trial. In this review, we intend to summarize mPGES-1 inhibitors focused on their inhibitory specificity with perspectives for future drug development.

Keywords: COX-2; Compound Ⅲ (PubChem CID: 67033699); Curcumin (PubChem CID: 969516); Dexamethasone (PubChem CID: 5743); EGCG (PubChem CID: 65064); Hyperforin (PubChem CID: 441298); ISC 27864 (PubChem CID: 136246033); Inflammatory disease; LY3031207 (PubChem CID: 57382526); MF-63 (PubChem CID: 16070041); MK886 (PubChem CID: 3651377); MPGES-1; MPGES-1 inhibitor; PGE(2); Phospholipid metabolism; Sinomenine (PubChem CID: 5459308).