Pyrrole alkanoic acid derivatives as nuisance inhibitors of microsomal prostaglandin E 2 synthase-1

Wiegard A., Hanekamp W., Griessbach K., Fabian J., Lehr M.

Zusammenfassung

Microsomal prostaglandin E 2 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 IC 50 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. © 2011 Elsevier Ltd. All rights reserved.