title: Design and Development of Microsomal Prostaglandin E2 Synthase-1 Inhibitors: Challenges and Future Directions.
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.
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University Jena , Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koeberle
authors.affiliation: Department of Pharmaceutical Chemistry, Pharmaceutical Institute, University of Tuebingen , Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University Jena , Philosophenweg 14, 07743 Jena, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D015232:Dinoprostone / Q000276:immunology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008958:Models, Molecular; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone