Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Microsomal Prostaglandin E2 Synthase-1 as a New Macromolecular Drug Target in the Prevention of Inflammation and Cancer

Author(s): Bahadır Bülbül and İlkay Küçükgüzel*

Volume 19, Issue 10, 2019

Page: [1205 - 1222] Pages: 18

DOI: 10.2174/1871520619666190227174137

Price: $65

Abstract

Background: Cancer is one of the most life-threatening diseases worldwide. Since inflammation is considered to be one of the known characteristics of cancer, the activity of PGE2 has been paired with different tumorigenic steps such as increased tumor cell proliferation, resistance to apoptosis, increased invasiveness, angiogenesis and immunosuppression.

Objective: It has been successfully demonstrated that inhibition of mPGES-1 prevented inflammation in preclinical studies. However, despite the crucial roles of mPGEs-1 and PGE2 in tumorigenesis, there is not much in vivo study on mPGES-1 inhibition in cancer therapy. The specificity of mPGEs-1 enzyme and its low expression level under normal conditions makes it a promising drug target with a low risk of side effects.

Methods: A comprehensive literature search was performed for writing this review. An updated view on PGE2 biosynthesis, PGES isoenzyme family and its pharmacology and the latest information about inhibitors of mPGES-1 have been discussed.

Results: In this study, it was aimed to highlight the importance of mPGES-1 and its inhibition in inflammationrelated cancer and other inflammatory conditions. Information about PGE2 biosynthesis, its role in inflammationrelated pathologies were also provided. We kept the noncancer-related inflammatory part short and tried to bring together promising molecules or scaffolds.

Conclusion: The information provided in this review might be useful to researchers in designing novel and potent mPGES-1 inhibitors for the treatment of cancer and inflammation.

Keywords: PGE2, mPGES-1, cancer, inflammation, angiogenesis, proliferation, migration, invasion, apoptosis, immunosuppression.

« Previous Next »
Graphical Abstract

[1]
Panathur, N.; Dalimba, U.; Koushik, P.V.; Alvala, M.; Yogeeswari, P.; Sriram, D.; Kumar, V. Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition. Eur. J. Med. Chem., 2013, 69, 125-138.
[2]
Kulabaş, N.; Tatar, E.; Özakpınar, Ö.B.; Özsavcı, D.; Pannecouque, C.; Clercq, E.D.; Küçükgüzel, İ. Synthesis and antiproliferative evaluation of novel 2-(4H-1,2,4-triazole-3-ylthio)acetamide derivatives as inducers of apoptosis in cancer cells. Eur. J. Med. Chem., 2016, 121, 58-70.
[3]
Ruan, D.; So, D.R. Prostaglandin E2 produced by inducable COX-2 and mPGEs-1 promoting cancer cell proliferation in vitro and in vivo. Life Sci., 2014, 116(1), 43-50.
[4]
Mancini, J.A.; Blood, K.; Guay, J.; Gordon, R.; Claveau, D.; Chan, C.C.; Riendeau, D. Cloning, expression, and up-regulation of inducible rat prostaglandin E synthase during lipopolysaccharide-induced pyresis and adjuvant-induced arthritis. J. Biol. Chem., 2001, 276(9), 4469-4475.
[5]
Murakami, M. Lipid mediators in life science. Exp. Anim., 2011, 60(1), 7-20.
[6]
Nakanishi, M.; Gokhale, V.; Meuillet, E.J.; Rosenberg, D.W. mPGEs-1 as a target for cancer suppression, a comrehensive invited review “Phospholipase A2 and Lipid Mediators”. Biochimie, 2010, 92(6), 660-664.
[7]
Mattila, S.; Tuominen, H.; Koivukangas, J.; Stenback, F. The terminal prostaglandin synthases mPGEs-1, mPGEs-2 and cPGEs are all overexpressed in human gliomas. Neuropathology, 2009, 29(2), 156-165.
[8]
Larsson, K.; Jakobsson, P.J. Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy in cancer treatment. Prostaglandins Other Lipid Mediat., 2015, 120, 161-165.
[9]
Hanaka, H.; Pawelzik, S.C.; Johnsen, J.I.; Rakonjac, M.; Terawaki, K.; Rasmuson, A.; Sveinbjörnsson, B.; Schumacher, M.C.; Hamberg, M.; Samuelsson, B.; Jakobsson, P.J. Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells. Proc. Natl. Acad. Sci. USA, 2009, 106(44), 18757-18762.
[10]
Salvado, M.D.; Alfranca, A.; Haeggström, J.Z.; Redondo, J.M. Prostanoids in tumor angiogenesis: therapeutic intervention beyond COX-2. Trends Mol. Med., 2012, 18(4), 233-243.
[11]
Ricciotti, E.; FitzGerald, G.A. Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol., 2011, 31(5), 986-1000.
[12]
Markovic, T.; Jakopin, Z.; Dolenc, M.S.; Rascan, I.M. Structural features of subtype-selective EP receptor modulators. Drug Discov. Today, 2017, 22(1), 57-71.
[13]
Sala, A.; Proschakc, E.; Steinhilberc, D.; Rovatia, E. Two-pronged approach to anti-inflammatory therapy through the modulation of the arachidonic acid cascade. Biochem. Pharmacol., 2018, 158, 161-173.
[14]
Koeberle, A.; Werz, O. Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders. Biochem. Pharmacol., 2015, 98(1), 1-15.
[15]
Aoki, T.; Narumiya, S. Prostaglandins and chronic inflammation. Trends Pharmacol. Sci., 2012, 33(6), 304-311.
[16]
Jakobsson, P.J.; Thoren, S.; Morgenstern, R.; Samuelsson, B. Identification of human prostaglandin E synthase: A microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc. Natl. Acad. Sci. USA, 1999, 96(13), 7220-7225.
[17]
Friesen, R.W.; Mancini, J.A. Microsomal prostaglandin E2 synthase-1 (MPGES-1): A novel therapotic Target. J. Med. Chem., 2008, 51(14), 4059-4067.
[18]
Chang, H.H.; Meuillet, E.J. Identification and development of mPGEs-1 inhibitors: Where we are at? Future Med. Chem., 2011, 3(15), 1909-1934.
[19]
Idborg, H.; Olsson, P.; Leclerc, P.; Raouf, J.; Jakobsson, P.J.; Korotkova, M. Effects of mPGEs-1 deletion on eicosanoid and fatty acid profiles in mice. Prostaglandins Other Lipid Mediat., 2013, 107, 18-25.
[20]
Koeberle, A.; Laufer, S.A.; Werz, O. Design and development of microsomal prostaglandin e2 synthase-1 ınhibitors: Challenges and future directions. J. Med. Chem., 2016, 59(13), 5970-5986.
[21]
Gurpinar, E.; Grizzle, W.E.; Piazza, G.A. COX-independent mechanisms of cancer chemoprevention by anti-inflammatory drugs. Front. Oncol., 2013, 11(3), 1-18.
[22]
Regulski, M.; Regulska, K.; Prukała, W.; Piotrowska, H.; Stanisz, B.; Murias, M. COX-2 inhibitors: A novel strategy in the management of breast cancer. Drug Discov. Today, 2016, 21(4), 598-615.
[23]
Sujith, K.V.; Rao, J.N.; Shetty, P.; Kalluraya, B. Regioselective reaction: Synthesis and pharmacological study of Mannich bases containing ibuprofen moiety. Eur. J. Med. Chem., 2009, 44(9), 3697-3702.
[24]
Kuklish, S.L.; Antonysamy, S.; Bhattachar, S.N.; Chandrasekhar, S.; Fisher, M.J.; Fretland, A.J.; Gooding, K.; Harvey, A.; Hughes, N.E.; Luz, J.G.; Manninen, P.R.; McGee, J.E.; Navarro, A.; Norman, B.H.; Partridge, K.M.; Quimby, S.J.; Schiffler, M.A.; Sloan, A.V.; Warshawsky, A.M.; York, J.S.; Yu, X.P. Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors. Bioorg. Med. Chem. Lett., 2016, 26(19), 4824-4828.
[25]
Akasaka, H.; So, S.P.; Ruan, K.H. Relationship of the topological distances and activities between mPGEs-1 and COX-2 versus COX-1: Implications of the different post-translational endoplasmic reticulum organizations of COX-1 and COX-2. Biochemistry, 2015, 54(23), 3707-3715.
[26]
Akasaka, H.; Ruan, K.H. Identification of the two-phase mechanism of arachidonic acid regulating inflammatory prostaglandin E2 biosynthesis by targeting COX-2 and mPGEs-1. Arch. Biochem. Biophys., 2016, 603, 29-37.
[27]
He, S.; Li, C.; Liu, Y.; Lai, L. Discovery of highly potent microsomal prostaglandin E2 synthase 1 inhibitors using the active conformation structural model and virtual screen. J. Med. Chem., 2013, 56(8), 3296-3309.
[28]
Lee, A.S.; Ellman, M.B.; Yan, D.; Kroin, J.S.; Cole, B.J.; Wijnen, A.J.V. Im, H.J. A current review of molecular mechanisms regarding osteoarthritis and pain. Gene, 2013, 527(2), 440-447.
[29]
He, S.; Wu, Y.; Yu, D.; Lai, L. Microsomal prostaglandin E synthase-1 exhibits one-third-of-the-sites reactivity. Biochem. J., 2011, 440(1), 13-21.
[30]
Gudis, K.; Tatsuguchi, A.; Wada, K.; Futagami, S.; Nagata, K.; Hiratsuka, T.; Shinji, Y.; Miyake, K.; Tsukui, T.; Fukuda, Y.; Sakamoto, C. Microsomal prostaglandin e synthase (MPGES-1), mPGEs-2 ve cytosolic PGES expression in human gastritis and gastric ulcer tissue. Lab. Invest., 2005, 85(2), 225-236.
[31]
Chaudhry, U.A.; Zhuang, H.; Crain, B.J.; Doré, S. Elevated microsomal prostaglandin-E synthase-1 in Alzheimer’s disease. Alzheimers Dement., 2008, 4(1), 6-13.
[32]
Korotkova, M.; Jakobsson, P.J. Microsomal prostaglandin E synthase-1 in rheumatic diseases. Front. Pharmacol., 2011, 1, 1-8.
[33]
Murakami, M.; Naraba, H.; Tanioka, T.; Semmyo, N.; Nakatani, Y.; Kojima, F.; Ikeda, T.; Fueki, M.; Ueno, A.; Ohishi, S.; Kudo, I. Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J. Biol. Chem., 2000, 275(42), 32783-32792.
[34]
Ding, K.; Zhou, Z.; Hou, S.; Yuan, Y.; Zhou, S.; Zheng, X.; Chen, J.; Loftin, C.; Zheng, F.; Zhan, C.G. Structure-based discovery of mPGEs-1 inhibitors suitable for preclinical testing in wild-type mice as a new generation of antiinflammatory drugs. Sci. Rep., 2018, 8(1), 1-9.
[35]
Kojima, F.; Kato, S.; Kawai, S. Prostaglandin E synthase in the pathophysiology of arthritis. Fundam. Clin. Pharmacol., 2005, 19(3), 255-261.
[36]
Sun, Y.; Jia, Z.; Yang, G.; Kakizoe, Y.; Liu, M.; Yang, K.T.; Liu, Y.; Yang, B.; Yang, T. Microsomal PGEs-2 deletion remarkably enhances liver injury in streptozotocin-treated mice via induction of GLUT2. J. Hepatol., 2014, 61(6), 1328-1336.
[37]
Yamada, T.; Takusagawa, F. PGH2 Degradation pathway catalyzed by GSH-heme complex bound microsomal prostaglandin E2 synthase type 2: The first example of a dual-function enzyme. Biochemistry, 2007, 46(28), 8414-8424.
[38]
Yoshimatsu, K.; Golijanin, D.; Paty, P.B.; Soslow, R.A.; Jakobsson, P.J.; DeLellis, R.A.; Subbaramaiah, K.; Dannenberg, A.J. Inducible microsomal prostaglandin E synthase is overexpressed in colorectal adenomas and cancer. Clin. Cancer Res., 2001, 7(12), 3971-3976.
[39]
Yoshimatsu, K.; Altorki, N.K.; Golijanin, D.; Zhang, F.; Jakobsson, P.J.; Dannenberg, A.J.; Subbaramaiah, K. Inducible prostaglandin E synthase is overexpressed in non-small cell lung cancer. Clin. Cancer Res., 2001, 7(9), 2669-2674.
[40]
Matsuda, H.; Hosono, K.; Tsuru, S.; Kurashige, C.; Sekiguchi, K.; Akira, S.; Uematsu, S.; Okamoto, H.; Majima, M. Roles of mPGES-1, an inducible prostaglandin E synthase, in enhancement of LPS-induced lymphangiogenesis in a mouse peritonitis model. Life Sci., 2015, 142, 1-7.
[41]
Numao, A.; Hosono, K.; Suzuki, T.; Hayashi, I.; Uematsu, S.; Akira, S.; Ogino, Y.; Kawauchi, H.; Unno, N.; Majima, M. The inducible prostaglandin E synthase mPGES-1 regulates growth of endometrial tissues and angiogenesis in a mouse implantation model. Biomed. Pharmacother., 2011, 65(1), 77-84.
[42]
Nakanishi, M.; Montrose, D.C.; Clark, P.; Nambiar, P.R.; Belinsky, G.S.; Claffey, K.P.; Xu, D.; Rosenberg, D.W. Genetic deletion of mPGES-1 suppresses intestinal tumorigenesis. Cancer Res., 2008, 68(9), 3251-3259.
[43]
Gudis, K.; Tatsuguchi, A.; Wada, K.; Hiratsuko, T.; Futagami, S.; Fukuda, Y.; Kiyama, T.; Tajiri, T.; Miyake, K.; Sakamoto, C. Clinical significance of prostaglandin E synthase expression in gastric cancer tissue. Hum. Pathol., 2007, 38(12), 1826-1835.
[44]
Sasaki, Y.; Nakatani, Y.; Hara, S. Role of microsomal prostaglandin E synthase-1- (MPGES-1)-derived prostaglandin E2 in kolon carcinogenesis. Prostagland. Other Lipid Mediat, 2015, 121(A), 42-45.
[45]
Wu, Y.C.; Su, L.J.; Wang, H.W.; Lin, C.F.J.; Hsu, W.H.; Chou, T.Y.; Huang, C.Y.F.; Lu, C.L.; Hsueh, C.T. Co-overexpression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 adversely affects the postoperative survival in non-small cell lung cancer. J. Thorac. Oncol., 2010, 5(8), 1167-1174.
[46]
Jain, S.; Chakraborty, G.; Raja, R.; Kale, S.; Kundu, G.C. Prostaglandin E2 regulates tumor angiogenesis in prostate cancer. Cancer Res., 2008, 68(19), 7750-7759.
[47]
Korotkova, M.; Jakobsson, P.J. Characterization of microsomal prostaglandin E Synthase 1 inhibitors. Basic Clin. Pharmacol. Toxicol., 2014, 114, 64-69.
[48]
Donnini, S.; Finetti, F.; Terzuoli, E.; Giachetti, A.; Iniguez, M.A.; Hanaka, H.; Fresno, M.; Radmark, O.; Ziche, M. EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity. Oncogene, 2012, 31, 3457-3466.
[49]
Finetti, F.; Terzuoli, E.; Giachetti, A.; Santi, R.; Villari, D.; Hanaka, H.; Radmark, O.; Ziche, M.; Donnini, S. mPGES-1 in prostate cancer controls stemness and amplifies epidermal growth factor receptor-driven oncogenicity. Endocr. Relat. Cancer, 2015, 22(4), 665-678.
[50]
Matsuo, Y.I. The role of mPGES-1 in inflammatory brain diseases. Biol. Pharm. Bull., 2017, 40(5), 557-563.
[51]
Qiu, J.; Shi, Z.; Jiang, J. Cyclooxygenase-2 in glioblastoma multiforme. Drug Discov. Today, 2017, 22(1), 148-156.
[52]
Kock, A.; Larsson, K.; Bergqvist, F.; Eissler, N.; Elfman, L.H.M.; Raouf, J.; Korotkova, M.; Johnsen, J.I.; Jakobsson, P.J.; Kogner, P. Inhibition of microsomal prostaglandin E synthase-1 in cancer-associated fibroblasts suppresses neuroblastoma tumor growth. EBioMedicine, 2018, 32, 84-92.
[53]
Larsson, K.; Kock, A.; Idborg, H.; Henriksson, M.A.; Martinsson, T.; Johnsen, J.I.; Korotkova, M.; Kogner, P.; Jakobsson, P.J. COX/MPGES-1/PGE2 pathway depicts an inflammatory dependent high risk neuroblastoma subset. Proc. Natl. Acad. Sci. USA, 2015, 112(26), 8070-8075.
[54]
Wang, D.; DuBois, R.N. Prostaglandins and cancer. Gut, 2006, 55(1), 115-122.
[55]
Wang, D.; Dubois, R.N. Eicosanoids and cancer. Nat. Rev. Cancer, 2010, 10(3), 181-193.
[56]
Zhang, F.; Liu, J.; Shi, J.S. Anti-inflammatory activities of resveratrol in the brain: Role of resveratrol in microglial activation. Eur. J. Pharmacol., 2010, 636(1-3), 1-7.
[57]
Terzi, M.; Altun, G.; Şena, S.; Kocaman, A.; Kaplan, A.A.; Yurt, K.K.; Kaplan, S. The use of non-steroidal anti-inflammatory drugs in neurological diseases. J. Chem. Neuroanat., 2018, 87, 12-24.
[58]
Takeuchi, C.; Matsumoto, Y.; Kohyama, K.; Uematsu, S.; Akira, S.; Yamagata, K.; Takemiya, T. Microsomal prostaglandin E synthase-1 aggravates inflammation and demyelination in a mouse model of multiple sclerosis. Neurochem. Int., 2013, 62(3), 271-280.
[59]
Akitake, Y.; Nakatani, Y.; Kamei, D.; Hosokawa, M.; Akatsu, H.; Uematsu, S.; Akira, S.; Kudo, I.; Hara, S.; Takahashi, M. Microsomal prostaglandin E synthase-1 is induced in Alzheimer’s disease and it’s deletion mitigates Alzheimer’s disease like pathology in a mouse model. J. Neurosci. Res., 2013, 91(7), 909-919.
[60]
Chen, L.; Yang, G.; Monslow, J.; Todd, L.; Cormodec, D.P.; Tang, J.; Grant, G.R.; DeLong, J.H.; Tang, S.Y.; Lawson, J.A.; Pure, E.; FitzGerald, G.A. Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice. Proc. Natl. Acad. Sci. USA, 2014, 111(18), 6828-6833.
[61]
Matsuo, Y.I. Microsomal prostaglandin E synthase-1 is involved in the brain ischemic injury. Inflamm. Regen., 2010, 30(1), 26-33.
[62]
Siljehav, V.; Hofstetter, A.O.; Jakobsson, P.J.; Herlenius, E. mPGES-1 and prostaglandin E2: Vital role in inflammation, hypoxic response, and survival. Pediatr. Res., 2012, 72(5), 460-467.
[63]
Pelletier, J.M.; Wildi, L.M.; Pelletier, J.P. Future therapeutics for osteoarthritis. Bone, 2012, 51(2), 297-311.
[64]
Soria, M.A.A.; Beaumont, G.H.; Rubio, J.M.; Calvo, E.; Santillana, J.; Egido, J.; Largo, R. Long-term NSAID treatment directly decreases COX-2 and mPGES-1 production in the articular cartilage of patients with osteoarthritis. Osteoarthritis Cartilage, 2008, 16(12), 1484-1493.
[65]
Bage, T.; Kats, A.; Lopez, B.S.; Morgan, G.; Nilsson, G.; Burt, I.; Korotkova, M.; Corbett, L.; Knox, A.J.; Pino, L.; Jakobsson, P.J.; Modeer, T.; Lindberg, T.Y. Expression of Prostaglangin E synthases in periodontitis. Immunolocalisation and cellular regulation. Am. J. Pathol., 2011, 178(4), 1676-1688.
[66]
Mbalaviele, G.; Pauley, A.M.; Shaffer, A.F.; Zweifel, B.S.; Mathialagan, S.; Mnich, S.J.; Nemirovskiy, O.V.; Carter, J.; Gierse, J.K.; Wang, J.L.; Vazquez, M.L.; Moore, W.M.; Masferrer, J.L. Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor. Biochem. Pharmacol., 2010, 79(10), 1445-1454.
[67]
Kim, M.; Lee, S.; Park, E.B.; Kim, K.J.; Lee, H.H.; Shin, J.S.; Fischer, K.; Koeberle, A.; Werz, O.; Lee, K.T.; Lee, J.Y. Hit-to-lead optimization of phenylsulfonyl hydrazides for a potent suppressor of PGE2 production: Synthesis, biological activity, and molecular docking study. Bioorg. Med. Chem. Lett., 2016, 26(1), 94-99.
[68]
Hanke, T.; Rörsch, F.; Thieme, T.M.; Ferreiros, N.; Schneider, G.; Geisslinger, G.; Proschak, E.; Grösch, S.; Zsilavecz, M.S. Synthesis and pharmacological characterization of benzenesulfonamides as dual species inhibitors of human and murine mPGES-1. Bioorg. Med. Chem., 2013, 21(24), 7874-7883.
[69]
Dorris, S.L.; Peebles, R.S. PGI2 as a regulator of inflammatory diseases. Mediators Inflamm., 2012, 2012, 1-9.
[70]
Jin, Y.; Smith, C.L.; Hu, L.; Campanale, K.M.; Stoltz, R.; Huffman, L.G.; McNearney, T.A.; Yang, X.Y.; Ackermann, B.L.; Dean, R.; Regev, A.; Landschulz, W. Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin E synthase 1 inhibitor, with celecoxib. Clin. Pharmacol. Ther., 2016, 99(3), 274-284.
[71]
Norman, B.H.; Fisher, M.J.; Schiffler, M.A.; Kuklish, S.L.; Hughes, N.E.; Czeskis, B.A.; Cassidy, K.C.; Abraham, T.L.; Alberts, J.J.; Atlas, D.L. Identification and mitigation of reactive metabolites of 2-aminoimidazole-containing microsomal prostaglandin E synthase-1 inhibitors terminated due to clinical drug-induced liver injury. J. Med. Chem., 2018, 61(5), 2041-2051.
[72]
Jin, Y.; Regev, A.; Kam, J.; Phipps, K.; Smith, C.; Henck, J.; Campanale, K.; Hu, L.; Hall, D.G.; Yang, X.Y.; Nakano, M.; McNearney, T.A.; Uetrecht, J.; Landschulz, W. Dose-dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor. Br. J. Clin. Pharmacol., 2018, 84(1), 179-188.
[73]
Leclerc, P.; Idborg, H.; Spahiud, L.; Larsson, C.; Nekhotiaeva, N.; Wannberg, J.; Stenberg, P.; Korotkova, M.; Jakobsson, J. Characterization of a human and murine mPGES-1 inhibitor and comparison to mPGES-1 genetic deletion in mouse models of inflammation. Prostaglandins Other Lipid Mediat., 2013, 107, 26-34.
[74]
Leclerc, P.; Pawelzik, S.C.; Idborg, H.; Spahiu, L.; Larsson, C.; Stenberg, P.; Korotkova, M.; Jakobsson, P.J. Characterization of a new mPGES-1 inhibitor in rat models of inflammation. Prostaglandins Other Lipid Mediat., 2013, 102-103, 1-12.
[75]
Zhou, Z.; Yuan, Y.; Zhou, S.; Ding, K.; Zheng, F.; Zhan, C.G. Selective inhibitors of human mPGES-1 from structure-based computational screening. Bioorg. Med. Chem. Lett., 2017, 27(16), 3739-3743.
[76]
Hamza, A.; Zhao, X.; Tong, M.; Tai, H.H.; Zhan, C.G. Novel human mPGES-1 inhibitors identified through structure-based virtual screening. Bioorg. Med. Chem., 2011, 19(20), 6077-6086.
[77]
Lauro, G.; Manfra, M.; Pedatella, S.; Fischer, K.; Cantone, V.; Terracciano, S.; Bertamino, A.; Ostacolo, C.; Monterrey, I.G.; Nisco, M.D.; Riccio, R.; Novellino, E.; Werz, O.; Campiglia, P.; Bifulco, G. Identification of novel microsomal prostaglandin E2 synthase-1(mPGES-1) lead inhibitors from fragment virtual screening. Eur. J. Med. Chem., 2017, 125, 278-287.
[78]
Luz, J.G.; Antonysamy, S.; Kuklish, S.L.; Condon, B.; Lee, M.R.; Allison, D.; Yu, X.P.; Chandrasekhar, S.; Backer, R.; Zhang, A.; Russell, M.; Chang, S.S.; Harvey, A.; Sloan, A.V.; Fisher, M.J. Crystal structures of mPGES-1 inhibitor complexes form a basis for the rational design of potent analgesic and anti-inflammatory therapeutics. J. Med. Chem., 2015, 58(11), 4727-4737.
[79]
Micco, S.D.; Terracciano, S.; Cantone, V.; Fischer, K.; Koeberle, A.; Foglia, A.; Riccio, R.; Werz, O.; Bruno, I.; Bifulco, G. Discovery of new potent molecular entities able to inhibit mPGES-1. Eur. J. Med. Chem., 2018, 143, 1419-1427.
[80]
Lee, K.; Pham, V.C.; Choi, M.J.; Kim, K.J.; Lee, K.T.; Han, S.G.; Yu, Y.G.; Lee, J.Y. Fragment-based discovery of novel and selective mPGES-1 inhibitors Part1: Identification of sulfonamido-1,2,3-triazole-4,5-dicarboxylic acid. Bioorg. Med. Chem. Lett., 2013, 23(1), 75-80.
[81]
Riendeau, D.; Aspiotis, R.; Ethier, D.; Gareau, Y.; Grimm, E.L.; Guay, J.; Guiral, S.; Juteau, H.; Mancini, J.A.; Methot, N.; Rubin, J.; Friesen, R.W. Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886. Bioorg. Med. Chem. Lett., 2005, 15(14), 3352-3355.
[82]
Cote, B.; Boulet, L.; Brideau, C.; Claveau, D.; Ethier, D.; Frenette, R.; Gagnon, M.; Giroux, A.; Guay, J.; Guiral, S.; Mancini, J.; Martins, E.; Masse, F.; Methot, N.; Riendeau, D.; Rubin, J.; Xu, D.; Yu, H.; Ducharme, Y.; Friesen, R.W. Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors. Bioorg. Med. Chem. Lett., 2007, 17(24), 6816-6820.
[83]
Xu, D.; Rowland, S.E.; Clark, P.; Giroux, A.; Bernard, C.B.; Guiral, S.; Salem, M.; Ducharme, Y.; Friesen, R.W.; Methot, N.; Mancini, J.; Audoly, L.; Riendeau, D. MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a selective microsomal prostaglandin E synthase-1 inhibitor. Relieves pyresis and pain in preclinical models of inflammation. J. Pharmacol. Exp. Ther., 2008, 326(3), 754-763.
[84]
Koeberle, A.; Northoff, H.; Werz, O. Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1. Mol. Cancer Ther., 2009, 8(8), 2348-2355.
[85]
Koeberle, A.; Bauer, J.; Verhoff, M.; Hoffmann, M.; Northoff, H.; Werz, O. Green tea epigallocatechin-3-gallate inhibits microsomal prostaglandin E2 synthase-1. Biochem. Biophys. Res. Commun., 2009, 388(2), 350-354.
[86]
Bauer, J.; Kuehnl, S.; Rollinger, J.M.; Scherer, O.; Northoff, H.; Stuppner, H.; Werz, O.; Koeberle, A. Carnosol and carnosic acids from Salvia officinalis inhibit microsomal prostaglandin E2 synthase-1. J. Pharmacol. Exp. Ther., 2012, 342, 169-176.
[87]
Zhou, H.; Liu, J.X.; Luo, J.F.; Cheng, C.S.; Leung, E.L.H.; Li, Y.; Hui, X.; Liu, Z.Q.; Chen, T.B.; Duan, F.G.; Dong, Y.; Zuo, Y.H.; Li, C.; Lio, C.K.; Li, T.; Luo, P.; Xie, Y.; Yao, X.J.; Wange, P.X.; Liu, L. Suppressing mPGES-1 expression by sinomenine ameliorates inflammation and arthritis. Biochem. Pharmacol., 2017, 142, 133-144.
[88]
Noha, S.M.; Fischer, K.; Koeberle, A.; Garscha, U.; Werz, O.; Schuster, D. Discovery of novel, non-acidic mPGES-1 inhibitorsby virtual screening with a multistep protocol. Bioorg. Med. Chem., 2015, 23(15), 4839-4845.
[89]
Muthukaman, N.; Deshmukh, S.; Sarode, N.; Tondlekar, S.; Tambe, M.; Pisal, D.; Shaikh, M.; Kattige, V.G.; Honnegowda, S.; Karande, V.; Kulkarni, A.; Jadhav, S.B.; Mahat, M.Y.A.; Gudi, G.S.; Joshi, N.K.; Gharat, L.A. Discovery of 2-((2-chloro -6- fluorophenyl) amino) -N- (3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4] dioxino [20,30:3,4] benzo [1,2-d] imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitor. Bioorg. Med. Chem. Lett., 2016, 26(24), 5977-5984.
[90]
Muthukaman, N.; Tambe, M.; Deshmukh, S.; Pisal, D.; Tondlekar, S.; Shaikh, M.; Sarode, N.; Kattige, V.G.; Pisat, M.P.; Sawant, P.; Honnegowda, S.; Karande, V.; Kulkarni, A.; Behera, D.; Jadhav, S.B.; Sangana, R.R.; Gudi, G.S.; Joshi, N.K.; Gharat, L.A. Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as potent and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-1. Bioorg. Med. Chem. Lett., 2017, 27(23), 5131-5138.
[91]
Muthukaman, N.; Deshmukh, S.; Tambe, M.; Pisal, D.; Tondlekar, S.; Shaikh, M.; Sarode, N.; Kattige, V.G.; Sawant, P.; Pisat, M.; Karande, V.; Honnegowda, S.; Kulkarni, A.; Behera, B.; Jadhav, S.B.; Sangana, R.R.; Gudi, G.S.; Joshi, N.K.; Gharat, L.A. Alleviating CYP and hERG liabilities by structure optimization of dihydrofuran-fused tricyclic benzo[d]imidazole series - Potent, selective and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-2. Bioorg. Med. Chem. Lett., 2018, 28(7), 1211-1218.
[92]
Shiro, T.; Takahashi, H.; Kakiguchi, K.; Inoue, Y.; Masuda, K.; Nagata, H.; Tobe, M. Synthesis and SAR study of imidazoquinolines as a novel structural class of microsomal prostaglandin E2 synthase-1 inhibitors. Bioorg. Med. Chem. Lett., 2012, 22(1), 285-288.
[93]
Kablaoui, N.; Patel, S.; Sharo, J.; Meian, D.; Hoffmaster, K.; Berlioz, F.; Vazqurez, M.L.; Moore, W.M.; Nugent, R.A. Novel benzoxazole inhibitors of MPGES-1. Bioorg. Med. Chem. Lett., 2013, 23(3), 907-911.
[94]
Kats, A.; Bage, T.; Georgsson, P.; Jonsson, J.; Quezada, H.C.; Gustaffson, A.; Jansson, L.; Lindberg, C.; Nasstrom, K.; Lindberg, T.Y. Inhibition of microsomal prostaglandin Esynthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and amerolites experimental periodontitis in vivo. FASEB J., 2017, 27(6), 2328-2341.
[95]
Shin, J.H.; Lee, Y.A.; Lee, J.K.; Lee, Y.B.; Cho, W.; Im, D.S.; Lee, J.H.; Yun, B.S.; Springer, J.E.; Gwag, B.J. Concurrent blockade of free radical and microsomal prostaglandin E synthase-1-mediated PGE2 production improves safety and efficacy in a Mouse model of amyotropic lateral sclerosis. J. Neurochem., 2012, 122(5), 952-961.
[96]
Banerjee, A.; Pawar, M.Y.; Patil, S.; Yadav, P.S.; Kadam, P.A.; Kattige, V.G.; Deshpande, D.S.; Pednekar, P.; Pisat, M.K.; Gharat, L.A. Development of 2-aryl substituted quinazolin-4(3H)-one,pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E2 synthase-1 inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(20), 4838-4844.
[97]
Micco, S.D.; Spatafora, C.; Cardullo, N.; Riccio, R.; Fischer, K.; Pergola, C.; Koeberle, A.; Werz, O.; Chalal, M.; Fasseur, D.V.; Tringali, C.; Bifulco, G. 2,3-Dihydrobenzofuran privileged structures as new bioinspired lead compounds for the design of mPGES-1 inhibitors. Bioorg. Med. Chem., 2016, 24(4), 820-826.
[98]
Koeberle, A.; Siemoneit, U.; Bühring, U.; Northoff, H.; Laufer, S.; Albrecht, W.; Werz, O. Licofelone suppresses prostaglandin E2 formation by interference with the inducible microsomal prostaglandin E2 synthase-1. J. Pharmacol. Exp. Ther., 2008, 326(3), 975-982.
[99]
Pelletier, J.M.; Lajeunesse, D.; Reboul, P.; Pelletier, J.P. Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Ann. Rheum. Dis., 2003, 62(6), 501-509.
[100]
Gür, Z.T.; Çalıskan, B.; Garscha, U.; Olgaç, A.; Schubert, U.S.; Gerstmeier, J.; Werz, O.; Banoglu, E. Identification of multi-target inhibitors of leukotriene and prostaglandin E2 biosynthesis by structural tuning of the FLAP inhibitor BRP-7. Eur. J. Med. Chem., 2018, 150, 876-899.

Rights & Permissions Print Cite
Article Metrics
69
5
© 2024 Bentham Science Publishers | Privacy Policy