Design and Development of Microsomal Prostaglandin E2 Synthase-1 Inhibitors: Challenges and Future Directions

Journal of Medicinal Chemistry
A KoeberleOliver Werz

Abstract

Microsomal prostaglandin E2 synthase (mPGES)-1 is responsible for the massive prostaglandin E2 (PGE2) formation during inflammation. Increasing evidence reveals mPGES-1 inhibitors as a safe alternative to nonsteroidal anti-inflammatory drugs. The first selective mPGES-1 inhibitors recently entered clinical trials. Major challenges for drug development have been the high plasma protein binding of lead structures, interspecies discrepancies, nuisance inhibition, sophisticated enzyme assays, and limited structural information about the mPGES-1 inhibitor binding site. Since most of these drawbacks could be solved during the past few years, we are standing at the threshold of a new era of mPGES-1-targeting anti-inflammatory drugs. This perspective introduces mPGES-1 as a key player within the network of eicosanoid biosynthesis and summarizes our current understanding of its structure and mechanism. Moreover, we present high-throughput and in silico screening techniques and discuss the structure-activity relationship and pharmacological potential of major mPGES-1 inhibitor classes in light of recent insights from pharmacophore models and cocrystallization studies.

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Citations

Dec 23, 2016·Expert Opinion on Therapeutic Patents·Oliver WerzUlrike Garscha
Dec 23, 2016·Medicinal Research Reviews·Catarina Pereira-LeiteSalette Reis
Jun 20, 2017·Expert Opinion on Therapeutic Patents·Anastasia PsarraGeorge Kokotos
Mar 3, 2017·Journal of Medicinal Chemistry·Ewgenij ProschakDaniel Merk
Mar 1, 2018·BMC Gastroenterology·Thorbjørn Søren Rønn JensenNiels Bindslev
Apr 18, 2019·The Journal of Pharmacology and Experimental Therapeutics·Lihong ChenGarret A FitzGerald
Nov 2, 2019·Science Translational Medicine·Carol Robertson-PlouchMatthew J Fisher
Nov 17, 2019·The Journal of Pharmacology and Experimental Therapeutics·Chao ZhangJinshan Cao
Mar 5, 2019·Anti-cancer Agents in Medicinal Chemistry·Bahadır Bülbül, İlkay Küçükgüzel
Dec 13, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sun-Hee KimElizabeth A Grimm
Aug 4, 2020·Journal of Molecular Biology·Madhuranayaki Thulasingam, Jesper Z Haeggström
May 29, 2021·Frontiers in Chemistry·Simone Di MiccoGiuseppe Bifulco

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