Aminothiazole-featured pirinixic acid derivatives as dual 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 inhibitors with improved potency and efficiency in vivo

Journal of Medicinal Chemistry

Volumn 56, Issue 22, 2013, Pages 9031-9044

  Hanke, Thomas ^a   Dehm, Friederike ^b   Liening, Stefanie ^b   Popella, Sven Desiderius ^b   MacZewsky, Jonas ^b,c   Pillong, Max ^f   Kunze, Jens ^f   Weinigel, Christina ^d   Barz, Dagmar ^d   Kaiser, Astrid ^a   Wurglics, Mario ^a   Lämmerhofer, Michael ^e   Schneider, Gisbert ^f   Sautebin, Lidia ^c   Schubert Zsilavecz, Manfred ^a   Werz, Oliver ^b  

^a GOETHE UNIVERSITY   (Germany)

^b FRIEDRICH SCHILLER UNIVERSITY JENA   (Germany)

^c UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^d JENA UNIVERSITY HOSPITAL   (Germany)

^e UNIVERSITY OF TÜBINGEN   (Germany)

^f ETH ZURICH   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

2 [(4 CHLORO 6 ((4 (NAPHTHALEN 2 YL) 1,3 THIAZOL 2 YL)AMINO)PYRIMIDIN 2 YL)SULFANYL]OCTANOIC ACID; ANTIINFLAMMATORY AGENT; ARACHIDONATE 5 LIPOXYGENASE; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; LIPOXYGENASE INHIBITOR; PEPTIDOLEUKOTRIENE; PIRINIXIC ACID; PROSTAGLANDIN E SYNTHASE 1; PROSTAGLANDIN INHIBITOR; THIAZOLE DERIVATIVE; UNCLASSIFIED DRUG; ZYMOSAN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; BINDING SITE; BLOOD VESSEL PERMEABILITY; CELL INFILTRATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG DESIGN; DRUG EFFICACY; DRUG METABOLISM; DRUG POTENCY; DRUG STRUCTURE; ENZYME ACTIVE SITE; ENZYME ACTIVITY; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IC 50; IN VIVO STUDY; INFLAMMATORY CELL; LIVER MICROSOME; MALE; MOUSE; NEUTROPHIL CHEMOTAXIS; NONHUMAN; PERITONITIS; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; ARACHIDONATE 5-LIPOXYGENASE; BINDING SITES; DRUG DESIGN; HUMANS; HYDROPHOBIC AND HYDROPHILIC INTERACTIONS; INHIBITORY CONCENTRATION 50; INTRAMOLECULAR OXIDOREDUCTASES; LIPOXYGENASE INHIBITORS; MALE; MICE; MICROSOMES; MODELS, MOLECULAR; PERITONITIS; PROTEIN CONFORMATION; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES; ZYMOSAN;

EID: 84889250812     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401557w     Document Type: Article

References (44)

1. Samuelsson, B.; Morgenstern, R.; Jakobsson, P.-J. Membrane prostaglandin E synthase-1: a novel therapeutic target Pharmacol. Rev. 2007, 59, 207-224 (Pubitemid 47481434)
2. Abdel-Tawab, M.; Zettl, H.; Schubert-Zsilavecz, M. Nonsteroidal anti-inflammatory drugs: a critical review on current concepts applied to reduce gastrointestinal toxicity Curr. Med. Chem. 2009, 16, 2042-2063
3. Jakobsson, P. J.; Thorén, 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. U. S. A. 1999, 96, 7220-7225 (Pubitemid 29299642)
4. Celotti, F.; Laufer, S. Anti-inflammatory drugs: new multitarget compounds to face an old problem. The dual inhibition concept Pharmacol. Res. 2001, 43, 429-436 (Pubitemid 32578858)
5. RaÌŠdmark, O.; Samuelsson, B. Microsomal prostaglandin E synthase-1 and 5-lipoxygenase: potential drug targets in cancer J. Int. Med. 2010, 268, 5-14
6. Werz, O.; Greiner, C.; Koeberle, A.; Hoernig, C.; George, S.; Popescu, L.; Syha, I.; Schubert-Zsilavecz, M.; Steinhilber, D. Novel and potent inhibitors of 5-lipoxygenase product synthesis based on the structure of pirinixic acid J. Med. Chem. 2008, 51, 5449-5453
7. Koeberle, A.; Rossi, A.; Zettl, H.; Pergola, C.; Dehm, F.; Bauer, J.; Greiner, C.; Reckel, S.; Hoernig, C.; Northoff, H.; Bernhard, F.; Dötsch, V.; Sautebin, L.; Schubert-Zsilavecz, M.; Werz, O. The molecular pharmacology and in vivo activity of 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2- ylthio)octanoic acid (YS121), a dual inhibitor of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase J. Pharmacol. Exp. Ther. 2010, 332, 840-848
8. Koeberle, A.; Zettl, H.; Greiner, C.; Wurglics, M.; Schubert-Zsilavecz, M.; Werz, O. Pirinixic acid derivatives as novel dual inhibitors of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase J. Med. Chem. 2008, 51, 8068-8076
9. Greiner, C.; Hörnig, C.; Rossi, A.; Pergola, C.; Zettl, H.; Schubert-Zsilavecz, M.; Steinhilber, D.; Sautebin, L.; Werz, O. 2-(4-(Biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52)-a novel type of 5-lipoxygenase inhibitor with favourable molecular pharmacology and efficacy in vivo Br. J. Pharmacol. 2011, 164, 781-793
10. Kats, A.; BaÌŠge, T.; Georgsson, P.; Jönsson, J.; Quezada, H. C.; Gustafsson, A.; Jansson, L.; Lindberg, C.; Näsström, K.; Yucel-Lindberg, T. Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo FASEB J. 2013, 27, 2328-2341
11. Cho, Y. S.; Kim, C. H.; Surh, J. H.; Kang, N. S.; Yoo, S. E.; Cheon, H. G. Identification of 4-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-2,6-dimethyl- phenol (KR-33749) as an inhibitor of 5-lipoxygenase with potent antiinflammatory activity Pharmacology 2010, 86, 65-72
12. Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Pd-catalyzed N -arylation of heteroarylamines Org. Lett. 2002, 4, 3481-3484
13. Lämmerhofer, M.; Pell, R.; Mahut, M.; Richter, M.; Schiesel, S.; Zettl, H.; Dittrich, M.; Schubert-Zsilavecz, M.; Lindner, W. Enantiomer separation and indirect chromatographic absolute configuration prediction of chiral pirinixic acid derivatives: limitations of polysaccharide-type chiral stationary phases in comparison to chiral anion-exchangers J. Chromatogr., A 2010, 1217, 1033-1040
14. Zettl, H.; Dittrich, M.; Steri, R.; Proschak, E.; Rau, O.; Steinhilber, D.; Schneider, G.; Lämmerhofer, M.; Schubert-Zsilavecz, M. Novel Pirinixic Acids as PPARa Preferential Dual PPARa/gAgonists QSAR Comb. Sci. 2009, 28, 576-586
15. Carter, G. W.; Young, P. R.; Albert, D. H.; Bouska, J.; Dyer, R.; Bell, R. L.; Summers, J. B.; Brooks, D. W. 5-Lipoxygenase inhibitory activity of zileuton J. Pharmacol. Exp. Ther. 1991, 256, 929-937
16. Claveau, D.; Sirinyan, M.; Guay, J.; Gordon, R.; Chan, C.-C.; Bureau, Y.; Riendeau, D.; Mancini, J. A. Microsomal prostaglandin E synthase-1 is a major terminal synthase that is selectively up-regulated during cyclooxygenase-2- dependent prostaglandin E2 production in the rat adjuvant-induced arthritis model J. Immunol. 2003, 170, 4738-4744 (Pubitemid 36519982)
17. Werz, O.; Steinhilber, D. Development of 5-lipoxygenase inhibitors-lessons from cellular enzyme regulation Biochem. Pharmacol. 2005, 70, 327-333 (Pubitemid 40908906)
18. 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, 975-982
19. Hieke, M.; Greiner, C.; Thieme, T. M.; Schubert-Zsilavecz, M.; Werz, O.; Zettl, H. A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl pirinixic acid scaffold Bioorg. Med. Chem. Lett. 2011, 21, 1329-1333
20. Feisst, C.; Pergola, C.; Rakonjac, M.; Rossi, A.; Koeberle, A.; Dodt, G.; Hoffmann, M.; Hoernig, C.; Fischer, L.; Steinhilber, D.; Franke, L.; Schneider, G.; RaÌŠdmark, O.; Sautebin, L.; Werz, O. Hyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivo Cell. Mol. Life Sci. 2009, 66, 2759-2771
21. Werz, O. Inhibition of 5-lipoxygenase product synthesis by natural compounds of plant origin Planta Med. 2007, 73, 1331-1357 (Pubitemid 350084452)
22. Werz, O.; Szellas, D.; Henseler, M.; Steinhilber, D. Nonredox 5-lipoxygenase inhibitors require glutathione peroxidase for efficient inhibition of 5-lipoxygenase activity Mol. Pharmacol. 1998, 54, 445-451 (Pubitemid 28368835)
23. Fischer, L.; Steinhilber, D.; Werz, O. Molecular pharmacological profile of the nonredox-type 5-lipoxygenase inhibitor CJ-13,610 Br. J. Pharmacol. 2004, 142, 861-868 (Pubitemid 39004096)
24. Pergola, C.; Dodt, G.; Rossi, A.; Neunhoeffer, E.; Lawrenz, B.; Northoff, H.; Samuelsson, B.; RaÌŠdmark, O.; Sautebin, L.; Werz, O. ERK-mediated regulation of leukotriene biosynthesis by androgens: a molecular basis for gender differences in inflammation and asthma Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 19881-19886
25. RaÌŠdmark, O.; Werz, O.; Steinhilber, D.; Samuelsson, B. 5-Lipoxygenase: regulation of expression and enzyme activity Trends Biochem. Sci. 2007, 32, 332-341 (Pubitemid 47021417)
26. Hieke, M.; Greiner, C.; Dittrich, M.; Reisen, F.; Schneider, G.; Schubert-Zsilavecz, M.; Werz, O. Discovery and biological evaluation of a novel class of dual microsomal prostaglandin E2 synthase-1/5-lipoxygenase inhibitors based on 2-[(4,6-diphenethoxypyrimidin-2-yl)thio]hexanoic acid J. Med. Chem. 2011, 54, 4490-4507
27. Najmanovich, R.; Kurbatova, N.; Thornton, J. Detection of 3D atomic similarities and their use in the discrimination of small molecule protein-binding sites Bioinformatics 2008, 24, i105-i111
28. Bernstein, F. C.; Koetzle, T. F.; Williams, G. J.; Meyer, E. F.; Brice, M. D.; Rodgers, J. R.; Kennard, O.; Shimanouchi, T.; Tasumi, M. The Protein Data Bank. A computer-based archival file for macromolecular structures Eur. J. Biochem. 1977, 80, 319-324 (Pubitemid 8218202)
29. Sjögren, T.; Nord, J.; Ek, M.; Johansson, P.; Liu, G.; Geschwindner, S. Crystal structure of microsomal prostaglandin E2 synthase provides insight into diversity in the MAPEG superfamily Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 3806-3811
30. Gilbert, N. C.; Bartlett, S. G.; Waight, M. T.; Neau, D. B.; Boeglin, W. E.; Brash, A. R.; Newcomer, M. E. The structure of human 5-lipoxygenase Science 2011, 331, 217-219
31. Weisel, M.; Proschak, E.; Schneider, G. PocketPicker: analysis of ligand binding-sites with shape descriptors Chem. Cent. J. 2007, 1, 7
32. Reisen, F.; Weisel, M.; Kriegl, J. M.; Schneider, G. Self-organizing fuzzy graphs for structure-based comparison of protein pockets J. Proteome Res. 2010, 9, 6498-6510
33. Jones, G.; Willett, P.; Glen, R. C. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation J. Mol. Biol. 1995, 245, 43-53
34. Hörnig, C.; Albert, D.; Fischer, L.; Hörnig, M.; RaÌŠdmark, O.; Steinhilber, D.; Werz, O. 1-Oleoyl-2-acetylglycerol Stimulates 5-Lipoxygenase Activity via a Putative (Phospho)lipid Binding Site within the N-terminal C2-like Domain J. Biol. Chem. 2005, 280, 26913-26921 (Pubitemid 41040726)
35. Kulkarni, S.; Das, S.; Funk, C. D.; Murray, D.; Cho, W. Molecular Basis of the Specific Subcellular Localization of the C2-like Domain of 5-Lipoxygenase J. Biol. Chem. 2002, 277, 13167-13174 (Pubitemid 34952687)
36. Hill, J. R. In Vitro Drug Metabolism Using Liver Microsomes. In Current Protocols in Pharmacology; 2003, 7.8.1-7.8.11. Enna, S. J.; Williams, M.; Ferkany, J. W., Kenakin, T., Porsolt, R. D., Sullivan, J. P., Eds.; John Wiley & Sons, Inc: Hoboken, NJ, 2001.
37. Riendeau, D.; Aspiotis, R.; Ethier, D.; Gareau, Y.; Grimm, E. L.; Guay, J.; Guiral, S.; Juteau, H.; Mancini, J. A.; Méthot, 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, 3352-3355 (Pubitemid 40835734)
38. De Simone, R.; Chini, M. G.; Bruno, I.; Riccio, R.; Mueller, D.; Werz, O.; Bifulco, G. Structure-based discovery of inhibitors of microsomal prostaglandin E2 synthase-1,5-lipoxygenase and 5-lipoxygenase-activating protein: promising hits for the development of new anti-inflammatory agents J. Med. Chem. 2011, 54, 1565-1575
39. Wang, J.; Limburg, D.; Carter, J.; Mbalaviele, G.; Gierse, J.; Vazquez, M. Selective inducible microsomal prostaglandin E(2) synthase-1 (mPGES-1) inhibitors derived from an oxicam template Bioorg. Med. Chem. Lett. 2010, 20, 1604-1609
40. Case, D.A.; Darden, T.A.; Cheatham, T.E., III; Simmerling, C.L.; Wang, J.; Duke, R.E.; Luo, R.; Walker, R.C.; Zhang, W.; Merz, K.M.; Roberts, B.; Hayik, S.; Roitberg, A.; Seabra, G.; Swails, J.; Goetz, A.W.; I. Kolossváry; Wong, K.F.; Paesani, F.; Vanicek, J.; Wolf, R.M.; Liu, J.; Wu, X.; Brozell, S.R.; Steinbrecher, T.; Gohlke, H.; Cai, Q.; Ye, X.; Wang, J.; Hsieh, M.-J.; Cui, G.; Roe, D.R.; Mathews, D.H.; Seetin, M.G.; R. Salomon-Ferrer; Sagui, C.; Babin, V.; Luchko, T.; Gusarov, S.; Kovalenko, A.;; Kollman, P.A.; AMBER 12; University of California: San Francisco, 2012.
41. Werz, O.; Bürkert, E.; Samuelsson, B.; RaÌŠdmark, O.; Steinhilber, D. Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorphonuclear leukocytes Blood 2002, 99, 1044-1052 (Pubitemid 34527142)
42. Fischer, L.; Szellas, D.; RaÌŠdmark, O.; Steinhilber, D.; Werz, O. Phosphorylation- and stimulus-dependent inhibition of cellular 5-lipoxygenase activity by nonredox-type inhibitors FASEB J. 2003, 17, 949-951
43. Rao, T. S.; Currie, J. L.; Shaffer, A. F.; Isakson, P. C. In vivo characterization of zymosan-induced mouse peritoneal inflammation J. Pharmacol. Exp. Ther. 1994, 269, 917-925 (Pubitemid 24204169)
44. Kolaczkowska, E.; Shahzidi, S.; Seljelid, R.; van Rooijen, N.; Plytycz, B. Early vascular permeability in murine experimental peritonitis is co-mediated by resident peritoneal macrophages and mast cells: crucial involvement of macrophage-derived cysteinyl-leukotrienes Inflammation 2002, 26, 61-71 (Pubitemid 34274484)