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

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is an enzyme, which is induced during the inflammatory response. Therefore, inhibitors of this enzyme are considered to be potential anti-inflammatory drugs. We have identified 3-(4-dodecanoyl-1,3,5-trimethylpyrrol-2-yl)propionic acid (12) as submicromolar inhibitor of mPGES-1. Surprisingly, structural variations made around this lead only resulted in a relatively small change of enzyme inhibitory potency. Such flat structure–activity relationships are reported to be typical for so called nuisance inhibitors, which exert their action not by directly binding to the enzyme, but by forming colloid-like aggregates at micromolar and sometimes submicromolar concentrations, which somehow sequester and inhibit enzyme targets without specificity. Since aggregate-based inhibition is highly sensitive to non-ionic detergents such as Triton X-100, we investigated some of our compounds for inhibition of human recombinant mPGES-1 also in presence of this detergent. The pyrrole derivatives 12, 67 and 81, which exhibited IC50 values in absence of Triton X-100 in the range of 0.1 and 1 μM, were virtually inactive at the highest test concentration of 10 μM when 0.1% of the detergent was added. In the same way, the published mPGES-1 inhibitor 2-[(4-{[(1,1′-biphenyl)-4-ylmethyl]amino}-6-chloropyrimidin-2-yl)thio]octanoic acid (Cay10589) (6) totally lost its activity under these conditions. Therefore, these compounds have to be judged as nuisance inhibitors of the enzyme. In contrast, the known indole derivative 3-[3-(tert-butylthio)-1-(4-chlorobenzyl)-5-isopropylindol-2-yl]-2,2-dimethylpropionic acid (MK-886) (2) showed a considerable activity (75% inhibition at 10 μM) also in the presence of Triton X-100.

Figure optionsDownload as PowerPoint slideHighlights
► Currently used assays for inhibitors of mPGES-1 may lead to false positive hits.
► Addition of Triton X-100 to the assay buffer avoids such misleading results.
► Published mPGES-1 inhibitors should be re-evaluated in presence of Triton X-100.