Arzneimittelforschung 2010; 60(8): 497-505
DOI: 10.1055/s-0031-1296318
Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs
Editio Cantor Verlag Aulendorf (Germany)

Synthesis of 1,5-diarylpyrazol-3-propanoic acids towards inhibition of cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4 formation

Burcu çaliŞkan Ergün
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, Ankara, Turkey
,
Maria Teresa Nuñe
2   Faes Farma, S.A., Departamanto de Investigacion, Bilbao, Spain
,
Luis Labeaga
2   Faes Farma, S.A., Departamanto de Investigacion, Bilbao, Spain
,
Francisco Ledo
2   Faes Farma, S.A., Departamanto de Investigacion, Bilbao, Spain
,
Janice Darlington
3   Amira Pharmaceuticals, San Diego, CA, USA
,
Gretchen Bain
3   Amira Pharmaceuticals, San Diego, CA, USA
,
Bilge çakir
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, Ankara, Turkey
,
Erden Banoglu
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, Ankara, Turkey
› Author Affiliations
Further Information

Publication History

Publication Date:
03 December 2011 (online)

Abstract

A set of 25 derivatives of 3-[1-(6-substi-tuted-pyridazin-3-yl)-5-(4-substituted-phenyl)-1H-pyrazol-3-yl]propanoic acid has been synthesized and evaluated for their in vitro cyclooxygenase-1/2 (COX-1 2) inhibitory activity using assays with purified COX-1 and COX-2 enzymes a well as for their 5-lipoxygenase (5-LO)-mediated LTB4 formation inhibitory activity using an assay with activated human polymorphonuclear leukocyte (PMNL). Among the synthesized compounds, especially 4g showed COX-1 (IC5 = 1.5µM) and COX-2 (IC5 = 1.6µM inhibitory activity, whereas compound 4 b and 4 f resulted in the inhibition of 5-LO-mediated LTB4 formation at 14 and 12µM IC5 values, respectively, without any significant inhibition on COX isoforms.

 
  • Reference

  • 1 Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002; 420: 860-7
  • 2 Nathan C. Points of control in inflammation. Nature. 2002; 420: 846-52
  • 3 Mehrabian M, Allayee H. 5-Lipoxygenase and atherosclero-sis. Curr Opin Lipidol. 2003; 14: 447-57
  • 4 Samuelsson B. Leukotrienes: mediators of immediate hy-persensitivity reactions and inflammation. Science 1983; 220: 568-75
  • 5 Weissmann G. Prostaglandins as modulators rather than mediators of inflammation. J Lipid Mediat. 1993; 6: 275-86
  • 6 Ding XZ, Hennig R, Adrian TE. Lipoxygenase and cyclo-oxygenase metabolism: new insights in treatment and chemoprevention of pancreatic cancer. Mol Cancer. 2003; 2: 10-
  • 7 Romano M, Claria J. Cyclooxygenase-2 and 5-lipoxygenas converging functions on cell proliferation and tumor an-giogenesis: implications for cancer therapy. Faseb J. 2003; 17: 1986-95
  • 8 Werz O, Steinhilber D. Therapeutic options for 5-lipoxy genase inhibitors. Pharmacol Ther. 2006; 112: 701-18
  • 9 Funk CD. Leukotriene modifiers as potential therapeutic for cardiovascular disease. Nat Rev Drug Discov. 2005; 4: 664-72
  • 10 Charlier C, Michaux C. Dual inhibition of cyclooxygenase-(COX-2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer non-steroidal anti-inflammatory drug. Eur Med Chem. 2003; 38: 645-59
  • 11 Maier TJ, Tausch L, Hoernig M, Coste O, Schmidt R, Angioni C et al. Celecoxib inhibits 5-lipoxygenas. Biochem Pharmacol. 2008; 76: 862-72
  • 12 Chintakunta VK, Akella V, Vedula MS, Mamnoor PK, Mishra P, Casturi SR et al. 3-O-substituted benzyl pyridazi-none derivatives as COX inhibitors. Eur J Med Chem. 2002; 37: 339-47
  • 13 Biancalani C, Giovannoni MP, Pieretti S, Cesari N, Grazia-no A, Vergelli C et al. Further studies on arylpiperazinyl alkyl pyridazinones: discovery of an exceptionally potent orally active, antinociceptive agent in thermally induced pain. J Med Chem. 2009; 52: 7397-409
  • 14 Giovannoni MP, Cesari N, Vergelli C, Graziano A, Biancala-ni C, Biagini P et al. 4-amino-5-substituted-3(2H)-pyrida zinones as orally active antinociceptive agents: synthesis and studies on the mechanism of action. J Med Chem. 2007; 50: 3945-53
  • 15 Banoglu E, Okcelik B, Kupeli E, Unlu S, Yesilada E, Amat M et al. Amide derivatives of [5-chloro-6-(2-chloro/fluoro-benzoyl)-2-benzoxazolinone-3-yl]acetic acids as potential analgesic and anti-inflammatory compound. Arch Pharm (Weinheim). 2003; 336: 251-7
  • 16 Banoglu E, Akoglu C, Unlu S, Kupeli E, Yesilada E, Sahin MF. Amide derivatives of [6-(5-methyl-3-phenylpyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acids as potential analgesic and anti-inflammatory compound. Arch Pharm (Weinheim). 2004; 337: 7-14
  • 17 Banoglu E, Akoglu C, Unlu S, Ergun BC, Kupeli E, Yesila-da E et al. Synthesis of amide derivatives of [6-(3,5-di methylpyrazol-1-yl)-3(2H)-pyridazinone-2-yl] acetic acid and their analgesic and anti-inflammatory properties. Arzneimittelforschung. 2005; 55(9): 520-7
  • 18 Banoglu E, Sukuroglu M, çalıskan BErgün, NacakBaytas S, Ay-par E, Ark M. Synthesis of the amide derivatives of 3-[1-(3-pyri-dazinyl)-5-phenyl-1H-pyrazole-3-yl]propanoic acids as potential analgesic compound. Turkish J Chem. 2007; 31: 677-87
  • 19 Unlu S, Banoglu E, Ito S, Niiya T, Eren G, Okcelik B et al. Synthesis, characterization and preliminary screening of regioisomeric 1-(3-pyridazinyl)-3-arylpyrazole and 1-(3 pyridazinyl)-5-arylpyrazole derivatives towards cyclooxy-genase inhibition. J Enzyme Inhib Med Chem. 2007; 22: 351-61
  • 20 Druey J, Meier K, Eichenberger K. Chemotherapeutic studies in the heterocyclic series. IV. Pyridazines. 1. Cyclic maleic and citraconic hydrazide. Helv Chim. Acta. 1954; 37: 121-33
  • 21 Abdel-magid AF, Harris BD, Maryanoff CA. Process for preparing 1,5-diaryl-3-substituted pyrazoles. US 6384233. 2002
  • 22 Murray W, Watcher MP. Synthesis and properties of aryl-1,3-dioxo carboxylic acid. J Org Chem. 1990; 55: 3424-26
  • 23 Murray W, Wachter MP. Regioselective synthesis of 1,5-dis ubstituted pyrazoles. EP0293221. 1988
  • 24 Murray W, Lalan P, Connolly PJ. The mechanism of forma tion of 6-aryl-4,6-dioxohexanoic acids from aryl ketone and succinic acid. Tetrahedron Lett. 1993; 34: 5189-92
  • 25 Wachter MP, Ferro MP. Pharmacologically active 1,5-dia ryl-3-substitutedpyrazoles and method for synthesizing the same. EP0248594. 1987
  • 26 Wachter MP, Murray WV. Pharmacologically active N-1 and C-5 heterocyclic pyrazoles and method for synthesiz-ing the same. US 524294. 1993
  • 27 Futaki N, Takahashi S, Yokoyama M, Arai I, Higuchi S, Otomo S. NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenas (COX-2) activity in vitro. Prostaglandins. 1994; 47: 55-9
  • 28 Janusz JM, Young PA, Ridgeway JM, Scherz MW, Enzwei-ler K, Wu LI et al. New cyclooxygenase-2/5-lipoxygenas inhibitors. 1. 7 tert-Buty1-2,3-dihydro-3,3-dimethylbenzo-furan derivatives as gastrointestinal safe antiinflammatory and analgesic agents: discovery and variation of the 5-keto substituent. J Med Chem. 1998; 41: 1112-23
  • 29 Ford-Hutchinson AW, Bray MA, Doig MV, Shipley ME, Smith MJ. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocyte. Nature. 1980; 286: 264-65
  • 30 Murray W, Wachter M, Barton D, Forero-Kelly Y. The regio-selective synthesis of tepoxalin, 3-[5-(4-chlorophenyl)-1-(4-metoxyphenyl)-3-pyrazolyl]-N-hydroxy-N-methylpro-panamide and related 1,5-diarylpyrazole anti-inflamma-tory agents. Synthesis. 1991; 18-20
  • 31 Singh SK, SrinivasaReddy M, Shivaramakrishna S, Ka-vitha D, Vasudev R, MosesBabu J et al. Modified reaction conditions to achieve high regioselectivity in the two component synthesis of 1,5-diarylpyrazole. Tetrahedron Lett. 2004; 45: 7679-82
  • 32 Dannhardt G, Laufer S. Structural approaches to explain the selectivity of COX-2 inhibitors: is there a common pharmacophore?. Curr Med Chem. 2000; 7: 1101-12