Discovery of dual target inhibitors against cyclooxygenases and leukotriene A4 hydrolyase.

Dual target inhibitors against COX-2 and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activities using enzyme assays and human whole blood assay. Introduction of small electron withdrawing groups like NO(2) and CF(3) in the ortho-position of the terminal phenyl ring was found to change the original single target LTA(4)H inhibitor to dual target LTA(4)H and COX-2 inhibitors. Compound 5a and 5m showed dual LTA(4)H and COX-2 inhibition activities in the enzyme assays and the HWB assay with IC(50) values in the micromolar to submicromolar range. As their activities in HWB assay were comparable to the two starting single target inhibitors, the two compounds are promising for further studies. The strategy used in the current study may be generally applicable to other dual target drug designs.

[1]  J. Brophy.  Cardiovascular risk associated with celecoxib. , 2005, The New England journal of medicine.

[2]  Qiao-Hong Chen,et al.  Synthesis and Structure−Activity Relationship Studies of 1,3-Diarylprop-2-yn-1-ones: Dual Inhibitors of Cyclooxygenases and Lipoxygenases , 2006 .

[3]  R. D. Dyer,et al.  Purification and characterization of prostaglandin H synthase-2 from sheep placental cotyledons. , 1995, Archives of biochemistry and biophysics.

[4]  A. Hopkins.  Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[5]  Richard Morphy,et al.  Fragments, network biology and designing multiple ligands. , 2007, Drug discovery today.

[6]  M. Percival,et al.  The discovery of rofecoxib, [MK 966, Vioxx, 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2-inhibitor. , 1999, Bioorganic & medicinal chemistry letters.

[7]  Jesper Z. Haeggström,et al.  Crystal structure of human leukotriene A4 hydrolase, a bifunctional enzyme in inflammation , 2001, Nature Structural Biology.

[8]  K. Seibert,et al.  Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[9]  L. Lai,et al.  Finding multiple target optimal intervention in disease-related molecular network , 2008, Molecular systems biology.

[10]  J. Gierse,et al.  Structure−Activity Relationship Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a Potent Inhibitor of Leukotriene A4 (LTA4) Hydrolase , 2000 .

[11]  Lawrence J Marnett,et al.  A Novel Mechanism of Cyclooxygenase-2 Inhibition Involving Interactions with Ser-530 and Tyr-385* , 2003, Journal of Biological Chemistry.

[12]  S. Iacobelli,et al.  Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. , 1994, The Journal of pharmacology and experimental therapeutics.

[13]  P. Connolly,et al.  N-hydroxyurea and hydroxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase. , 1999, Bioorganic & medicinal chemistry letters.

[14]  Richard Morphy,et al.  Designed Multiple Ligands. An Emerging Drug Discovery Paradigm , 2006 .

[15]  Luhua Lai,et al.  Discovery of multitarget inhibitors by combining molecular docking with common pharmacophore matching. , 2008, Journal of medicinal chemistry.

[16]  Jesper Z Haeggström,et al.  Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: implications for M1 aminopeptidases and inhibitor design. , 2008, Chemistry & biology.

[17]  Richard Morphy,et al.  Designing multiple ligands - medicinal chemistry strategies and challenges. , 2009, Current pharmaceutical design.

[18]  G. Moore,et al.  4-nitro-2-phenoxymethanesulfonanilide (R-805): a chemically novel anti-inflammatory agent. , 1976, Archives internationales de pharmacodynamie et de therapie.

[19]  Dairong Wang,et al.  Cardiovascular hazard and non-steroidal anti-inflammatory drugs. , 2005, Current opinion in pharmacology.

[20]  R. Copeland,et al.  Mechanism of selective inhibition of the inducible isoform of prostaglandin G/H synthase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Richard Morphy,et al.  From magic bullets to designed multiple ligands. , 2004, Drug discovery today.

[22]  Mate S. Szalay,et al.  How to design multi-target drugs , 2007, Expert opinion on drug discovery.

[23]  Péter Csermely,et al.  The efficiency of multi-target drugs: the network approach might help drug design. , 2004, Trends in pharmacological sciences.

[24]  J. Falgueyret,et al.  Detergents profoundly affect inhibitor potencies against both cyclo-oxygenase isoforms. , 2004, The Biochemical journal.

[25]  J. Young,et al.  Human whole blood assays for inhibition of prostaglandin G/H synthases-1 and-2 using A23187 and lipopolysaccharide stimulation of thromboxane B2 production , 1996, Inflammation Research.

[26]  H. Ye,et al.  Synthesis of N-alkyl glycine amides as potent inhibitors of leukotriene A4 hydrolase. , 2008, Bioorganic & Medicinal Chemistry Letters.

[27]  R. S. Rogers,et al.  Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib). , 1997, Journal of medicinal chemistry.

[28]  M. Suresh,et al.  Synthesis of celecoxib analogues possessing a N-difluoromethyl-1,2-dihydropyrid-2-one 5-lipoxygenase pharmacophore: biological evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity. , 2009, Journal of medicinal chemistry.

[29]  B. Psaty,et al.  COX-2 inhibitors--lessons in drug safety. , 2005, The New England journal of medicine.

[30]  Debashis Singh,et al.  FDA to review risks of antidepressants in adults , 2004, BMJ : British Medical Journal.

[31]  A. K. Katz,et al.  THE 2.0 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF PROSTAGLANDIN H(2) SYNTHASE-1: STRUCTURAL INSIGHTS INTO AN UNUSUAL PEROXIDASE , 2004 .

[32]  J. Haeggström,et al.  Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase. , 2008, Bioorganic & medicinal chemistry.

[33]  J. Pelletier,et al.  Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs , 2003, Annals of the rheumatic diseases.

[34]  Luhua Lai,et al.  Dynamic Simulations on the Arachidonic Acid Metabolic Network , 2007, PLoS Comput. Biol..

[35]  R. Hunt,et al.  The gastrointestinal safety of the COX-2 selective inhibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events , 2003, American Journal of Gastroenterology.