Structure-activity relationship of nonacidic quinazolinone inhibitors of human microsomal prostaglandin synthase 1 (mPGES 1)

Title:

Structure-activity relationship of nonacidic quinazolinone inhibitors of human microsomal prostaglandin synthase 1 (mPGES 1)

Author: Rörsch, F;Buscató, E;Deckmann, K;Schneider, G;Schubert-Zsilavecz, M;Geisslinger, G;Proschak, E;Grösch, S;
Year: 2012
Journal: J. Med. Chem.
Page: 3792-803
Volume: 55
Issue: 8
PubMed ID: 22449023
Abstract: Microsomal prostaglandin E synthase 1 (mPGES-1) is a key enzyme of the arachidonic acid cascade. Its product PGE(2) plays an important role in various inflammatory processes, pain, fever, and cancer. Selective inhibition of mPGES-1 might be a promising step to avoid cyclooxygenase-related effects of NSAIDs. We studied a class of quinazolinone derivatives of the lead structure FR20 for their effects on the isolated human and murine enzymes, human HeLa cells, and in various settings of the whole blood assay. Novel compounds with direct enzyme inhibiting activity in the submicromolar range (IC(50): 0.13-0.37 μM) were designed using a bioisosteric replacement strategy and proved to be effective in both cells and human whole blood. Furthermore, pharmacological profiling of toxicity and eicosanoid screening with LC/MS-MS was applied to characterize this new class of mPGES-1 inhibitors.
Impact Factor: 5.5
Link: http://pubs.acs.org/doi/abs/10.1021/jm201687d
Date: 4/26/2012
Email: Roersch@em.uni-frankfurt.de
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