Pyrrole alkanoic acid derivatives as nuisance inhibitors of microsomal prostaglandin E2 synthase-1

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

“…Variation of the concentration of PGH 2 substrate and GSH co-substrate provides insights into the kinetics/modes of inhibition, and inhibitor wash-out experiments might reveal reversibility of mPGES-1 interference. Inclusion of the non-ionic detergent triton-X100 (0.01-0.1%) in these assays allows to exclude nuisance inhibition, which is relevant for highly lipophilic compounds with strong tendency to form colloid-like aggregates which sequester and inhibit mPGES-1 without specific binding to the enzyme [65]. Series of nuisance inhibitors exhibit flat structure-activity relationships despite significant structural modifications.…”

Passerini/Tsuji–Trost Strategy towards Pyrrole Derivatives

“…However, pyrroles are found in various natural compounds and many uses of pyrroles as anticancer, antitubercular, or anti‐inflammatory agents are reported in the literature . In particular, families of pyrroles with similar structural patterns as the products prepared in our study have shown potential as cytosolic phospholipase A2 inhibitor ( 4 , Scheme ), histone deacetylase inhibitor ( 5 , Scheme ), or prostaglandin synthetase inhibitor ( 6 , Scheme ) . Numerous synthetic approaches have been proposed for pyrroles since their first preparation at the end of the 19th century, in which enamines play a key role as shown by their involvement in Hantzsch pyrrole synthesis .…”

Inhibitors of the Arachidonic Acid Cascade: Interfering with Multiple Pathways

“…) was identified and characterized in vitro in a library of pirinixic acid‐derived compounds, which are known as privileged scaffold for fatty acid mimetics . Although mPGES‐1 inhibition by pirinixic acids derivatives can be reversed by addition of detergents in vitro , the in vivo evaluation indicates potent anti‐inflammatory activity mediated by inhibition of multiple targets. Despite of the low micromolar activity, YS121 was already effective in a carrageenan‐induced pleurisy in rats at 1.5 mg/kg i.p.…”