Characterization of Microsomal Prostaglandin E Synthase 1 Inhibitors (original) (raw)
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Current Medicinal Chemistry, 2009
Cyclooxygenases (COX-1 and COX-2) catalyze the conversion of arachidonic acid (AA) into PGH 2 that is further metabolized by terminal prostaglandin (PG) synthases into biologically active PGs, for example, prostaglandin E 2 (PGE 2), prostacyclin I 2 (PGI 2), thromboxane A 2 (TXA 2), prostaglandin D 2 (PGD 2), and prostaglandin F 2 alpha (PGF 2α). Among them, PGE 2 is a widely distributed PG in the human body, and an important mediator of inflammatory processes. The successful modulation of this PG provides a beneficial strategy for the potential anti-inflammatory therapy. For instance, nonsteroidal antiinflammatory agents (NSAIDs), both classical nonselective (cNSAIDs) and the selective COX-2 inhibitors (coxibs) attenuate the generation of PGH 2 from AA that in turn reduces the synthesis of PGE 2 and modifies the inflammatory conditions. However, the long-term use of these agents causes severe side effects due to the nonselective inhibition of other PGs, such as PGI 2 and TXA 2 , etc. Microsomal prostaglandin E 2 synthase-1 (mPGES-1), a downstream PG synthase, specifically catalyzes the biosynthesis of COX-2derived PGE 2 from PGH 2 , and describes itself as a valuable therapeutic target for the treatment of acute and chronic inflammatory disease conditions. Therefore, the small molecule inhibitors of mPGES-1 would serve as a beneficial anti-inflammatory therapy, with reduced side effects that are usually associated with the nonselective inhibition of PG biosynthesis.
Chemical Biology & Drug Design, 2010
In our recent studies, we focused our attention on the synthesis of several gamma-hydroxybutenolides designed on the basis of petrosaspongiolide M 1 (PM) structure that has been recognized to potently inhibit the inflammatory process through the selective PLA(2) enzyme inhibition. By means of a combination of computational methods and efficient synthetic strategies, we generated small collections of PM modified analogs to identify new potent PLA(2) inhibitors, suitable for clinical development. In the course of the biological screening of our compounds, we discovered a potent and selective inhibitor of mPGES-1 expression, the benzothiophene gamma-hydroxybutenolide 2, which so far represents the only product, together with resveratrol, able to reduce PGE(2) production through the selective downregulation of mPGES-1 enzyme. In consideration that microsomal prostaglandin E synthase 1 (mPGES-1) is one of the most strategic target involved both in inflammation and in carcinogenesis processes, we decided to explore the biological effects of some structural changes of the gamma-hydroxybutenolide 2, hoping to improve its biological profile. This optimization process led to the identification of three strictly correlated compounds 14g, 16g, and 18 with higher inhibitory potency on PGE(2) production on mouse macrophage cell line RAW264.7 through the selective modulation of mPGES-1 enzyme expression.
Journal of Medicinal Chemistry, 2011
Microsomal prostaglandin E(2) synthase-1 (mPGES-1) catalyzes prostaglandin E(2) formation and is considered as a potential anti-inflammatory pharmacological target. To identify novel chemical scaffolds active on this enzyme, two pharmacophore models for acidic mPGES-1 inhibitors were developed and theoretically validated using information on mPGES-1 inhibitors from literature. The models were used to screen chemical databases supplied from the National Cancer Institute (NCI) and the Specs. Out of 29 compounds selected for biological evaluation, nine chemically diverse compounds caused concentration-dependent inhibition of mPGES-1 activity in a cell-free assay with IC(50) values between 0.4 and 7.9 μM, respectively. Further pharmacological characterization revealed that also 5-lipoxygenase (5-LO) was inhibited by most of these active compounds in cell-free and cell-based assays with IC(50) values in the low micromolar range. Together, nine novel chemical scaffolds inhibiting mPGES-1 are presented that may possess anti-inflammatory properties based on the interference with eicosanoid biosynthesis.
Targeting inflammation: multiple innovative ways to reduce prostaglandin E2
Pharmaceutical Patent Analyst, 2013
The PGE2 pathway is important in inflammation-driven diseases and specific targeting of the inducible mPGES-1 is warranted due to the cardiovascular problems associated with the long-term use of COX-2 inhibitors. This review focuses on patents issued on methods of measuring mPGES-1 activity, on drugs targeting mPGES-1 and on other modulators of free extracellular PGE2 concentration. Perspectives and conclusions regarding the status of these drugs are also presented. Importantly, no selective inhibitors targeting mPGES-1 have been identified and, despite the high number of published patents, none of these drugs have yet made it to clinical trials.
2020
Prostaglandin E 2 (PGE 2) plays a critical role in eliciting inflammation. Non-steroidal antiinflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE 2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastro-intestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiological functions. Microsomal prostaglandin E 2 synthase (mPGES-1) is a membrane bound terminal enzyme in the prostanoid pathway, which acts downstream of cyclooxygenase 2 and is responsible for PGE 2 production during inflammation. Thus inhibition of this enzyme would be expected to block PGE 2 production without inhibiting other prostanoids and would provide analgesic efficacy without the side-effects. In this report, we describe novel mPGES-1 inhibitors that are potent in blocking PGE 2 production and are efficacious in a guinea pig monoiodoacetate model of arthralgia. These molecules may be useful in treating the signs and symptoms associated with arthritis.
Location of Inhibitor Binding Sites in the Human Inducible Prostaglandin E Synthase, MPGES1
Biochemistry, 2011
The inducible microsomal prostaglandin E 2 synthase 1 (MPGES1) is an integral membrane protein co-expressed with and functionally coupled to cyclooxygenase 2 (COX-2) generating the pro-inflammatory molecule PGE 2 . The development of effective inhibitors of MPGES1 holds promise as a highly selective route to control inflammation. In this paper we describe the use of backbone amide H/D exchange mass spectrometry to map the binding sites of different types of inhibitors of MPGES1. The results reveal the locations of specific inhibitor binding sites which include the GSH binding site and a hydrophobic cleft in the protein thought to accommodate the prostaglandin H 2 substrate. In the absence of three-dimensional crystal structures of the enzymebound inhibitors, the results provide clear physical evidence that three pharmacologically active inhibitors bind in a hydrophobic cleft composed of sections of trans-membrane helices Ia, IIb, IIIb and IVb at the interface of subunits in the trimer. In principle, the H/D exchange behavior of the protein can be used as a preliminary guide for optimization of inhibitor efficacy. Finally, a comparison of the structures and H/D exchange behavior of MPGES1 and the related enzyme MGST1 in the presence of glutathione and the inhibitor glutathione sulfonate confirm the unusual observation that two proteins from the same superfamily harbor GSH binding sites in different locations.
Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target
Pharmacological Reviews, 2007
Prostaglandin E 2 (PGE 2) is the most abundant prostaglandin in the human body. It has a large number of biological actions that it exerts via four types of receptors, EP1-4. PGE 2 is formed from arachidonic acid by cyclooxygenase (COX-1 and COX-2)-catalyzed formation of prostaglandin H 2 (PGH 2) and further transformation by PGE synthases. The isomerization of the endoperoxide PGH 2 to PGE 2 is catalyzed by three different PGE synthases, viz. cytosolic PGE synthase (cPGES) and two membranebound PGE synthases, mPGES-1 and mPGES-2. Of these isomerases, cPGES and mPGES-2 are constitutive enzymes, whereas mPGES-1 is mainly an induced isomerase. cPGES uses PGH 2 produced by COX-1 whereas mPGES-1 uses COX-2-derived endoperoxide. mPGES-2 can use both sources of PGH 2. mPGES-1 is a
Identification of novel mPGES-1 inhibitors through screening of a chemical library
Bioorganic & Medicinal Chemistry Letters, 2012
Human microsomal prostaglandin E synthase-1 (mPGES-1) is an emerging drug target for inflammatory disorders and cancer suppression. Therefore, it is crucially important to discover mPGES-1 inhibitors with novel structural scaffolds for the development of anti-inflammatory drugs. Here, we report the mPGES-1 inhibitors identified through screening of a chemical library. Initial screening of 1841 compounds out of 200,000 in a master library resulted in 9 primary hits. From the master library, 387 compounds that share the scaffold structure with the 9 primary hit compounds were selected, of which 3 compounds showed strong inhibitory activity against mPGES-1 having IC 50 values of 1-3 lM. Notably, a derivative of sulfonylhydrazide, compound 3b, inhibited the LPS-induced PGE 2 production in RAW 264.7 cells. This compound showed novel scaffold structure compared to the known inhibitors of mPGES-1, suggesting that it could be further developed as a potent mPGES-1 inhibitor.