Identification of new γ-hydroxybutenolides that preferentially inhibit the activity of mPGES-1.
Microsomal prostaglandin E(2) synthase-1 (mPGES-1) has been recognized as novel, promising drug target for anti-inflammatory and anticancer drugs. mPGES-1 catalyzes the synthesis of the inducible prostaglandin E(2) in response to pro-inflammatory stimuli, rendering this enzyme extremely interesting in drug discovery process owing to the drastic reduction of the severe side effects typical for traditional non-steroidal anti-inflammatory drugs. In the course of our investigations focused on this topic, we identified two interesting molecules bearing the γ-hydroxybutenolide scaffold which potently inhibit the activity of mPGES-1. Notably, the lead compound 2c that inhibited mPGES-1 with IC(50) = 0.9 μM, did not affect other related enzymes within the arachidonic acid cascade.
Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy.
Rosa
R
De Simone
Ines
I
Bruno
Raffaele
R
Riccio
Katharina
K
Stadler
Julia
J
Bauer
Anja M
AM
Schaible
Stefan
S
Laufer
Oliver
O
Werz
D015107:4-Butyrolactone / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015107:4-Butyrolactone