Chemistry and biology of microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors as novel anti-inflammatory agents: recent developments and current status

Abstract

Prostaglandin (PG) E₂, a key mediator of inflammatory pain and fever, is biosynthesized from PGH₂ by microsomal prostaglandin E₂ synthase-1 (mPGES-1). During inflammation the expression of mPGES-1 increases resulting in increased PGE₂ formation. Specific inhibition of mPGES-1 reduces the biosynthesis of PGE₂, sparing other physiologically important PGs such as prostacyclin (PGI₂) and thromboxane A₂ (TXA₂). Inhibition of mPGES-1 might be superior over the inhibition of cyclooxygenases (COX), as the latter leads to the suppression of PGI₂, TXA₂ along with the pathogenic PGE₂ resulting in gastro-intestinal, renal and cardiovascular complications. Therefore, inhibition of mPGES-1 has been proposed as a promising approach for the development of drugs for inflammation and pain therapy, which only suppresses PGE₂ biosynthesis, avoiding the side effects caused by nonsteroidal anti-inflammatory drugs (NSAIDs) and specific COX-2 inhibitors. The current review article includes natural and synthetic inhibitors of mPGES-1 reported since 2000 with their in vitro activity (IC₅₀ values), in vivo activity, the status of clinical candidates, and critical appraisal of these reported inhibitors.