Fluorinated dual antithrombotic compounds based on 1,4-benzoxazine scaffold

European Journal of Medicinal Chemistry

Volumn 50, Issue , 2012, Pages 255-263

  Ilić, Miloš ^a   Kikelj, Danijel ^a   Ilaš, Janez ^a  

^a UNIVERSITY OF LJUBLJANA   (Slovenia)

Author keywords

1,4 Benzoxazine; Designed dual ligands; Fibrinogen receptor antagonists; Platelet aggregation; Thrombin inhibitor

Indexed keywords

2 [[2 [(4 CARBAMIMIDOYLPHENOXY)METHYL] 2,4 DIMETHYL 3,4 DIHYDRO 2H 1,4 BENZOXAZIN 7 YL](4 FLUOROBENZYL)AMINO] 2 OXOACETIC ACID; 4 [[6 [(4 FLUOROBENZYL)AMINO] 2,4 DIMETHYL 3,4 DIHYDRO 2H 1,4 BENZOXAZIN 2 YL]METHOXY]BENZONITRILE; ANTICOAGULANT AGENT; BENZOXAZINE DERIVATIVE; BLOOD CLOTTING FACTOR 10A; ETHYL 2 [[2 [(4 CARBAMIMIDOYLPHENOXY)METHYL] 2,4 DIMETHYL 3,4 DIHYDRO 2H 1,4 BENZOXAZIN 6 YL](3,4 DIFLUOROBENZYL)AMINO]ACETATE; ETHYL 2 [[2 [(4 CYANOPHENOXY)METHYL] 2,4 DIMETHYL 3,4 DIHYDRO 2H 1,4 BENZOXAZIN 6 YL](4 FLUOROBENZYL)AMINO]ACETATE; ETHYL 2 [[2 [(4 CYANOPHENOXY)METHYL] 2,4 DIMETHYL 3,4 DIHYDRO 2H 1,4 BENZOXAZIN 7 YL](3,5 DIFLUOROBENZYL)AMINO] 2 OXOACETATE; FIBRINOGEN RECEPTOR; FIBRINOGEN RECEPTOR ANTAGONIST; THROMBIN; TRYPSIN; UNCLASSIFIED DRUG; ANTITHROMBOCYTIC AGENT; HEMOSTATIC AGENT;

ANTICOAGULATION; ARTICLE; BINDING KINETICS; CARBON NUCLEAR MAGNETIC RESONANCE; COMPETITIVE INHIBITION; CYCLIZATION; DEFLUORINATION; DRUG POTENCY; FLUORINATION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HYDROLYSIS; IC 50; METHYLATION; MITSUNOBU REACTION; MOLECULAR DOCKING; MOLECULAR MODEL; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG EFFECT; HALOGENATION; HUMAN; METABOLISM; THROMBOCYTE AGGREGATION;

BENZOXAZINES; HALOGENATION; HEMOSTATICS; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBIN;

EID: 84858443749     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2012.01.059     Document Type: Article

References (18)

1. The Global Burden of Disease: 2004 Update 2008 World Health Organization Geneva, Switzerland
2. A. Schwienhorst Direct thrombin inhibitors - a survey of recent developments Cell Mol. Life. Sci. 63 2006 2773 2791
3. J.W. Eikelboom, and J. Hirsh Combined antiplatelet and anticoagulant therapy: clinical benefits and risks J. Thromb. Haemost. 5 Suppl. 1 2007 255 263
4. J. Ilaš, Z. Jakopin, T. Borštnar, M. Stegnar, and D. Kikelj 3,4-Dihydro-2H-1,4-benzoxazine derivatives combining thrombin inhibitory and glycoprotein IIb/IIIa receptor antagonistic activity as a novel class of antithrombotic compounds with dual function J. Med. Chem. 51 2008 5617 5629
5. P. Stefanič Anderluh, M. Anderluh, J. Ilaš, J. Mravljak, M. Sollner Dolenc, M. Stegnar, and D. Kikelj Toward a novel class of antithrombotic compounds with dual function. Discovery of 1,4-benzoxazin-3(4H)- one derivatives possessing thrombin inhibitory and fibrinogen receptor antagonistic activities J. Med. Chem. 48 2005 3110 3113
6. J. Ilaš, F. Hudecz, H. Suli-Vargha, and D. Kikelj Peptides and pseudopeptides incorporating d-Phe-Pro-Arg and Arg-Gly-Asp lead sequences as potential antithrombotic agents J. Pept. Sci. 14 2008 946 953
7. J.K. Mishra, K. Samanta, M. Jain, M. Dikshit, and G. Panda Amino acid based enantiomerically pure 3-substituted benzofused heterocycles: a new class of antithrombotic agents Bioorg. Med. Chem. Lett. 20 2010 244 247
8. J. Ilaš, P. Štefanič, M.S. Dolenc, and D. Kikelj Recent advances in the synthesis of 2H-1,4-benzoxazin-3-(4H)-ones and 3,4-dihydro-2H-1,4-benzoxazines Tetrahedron 61 2005 7325 7348
9. for review see: M. Ilić, D. Kikelj, and J. Ilaš Multitarget antithrombotic drugs Curr. Top. Med. Chem. 11 2011 2834 2848
10. J.A. Olsen, D.W. Banner, P. Seiler, B. Wagner, T. Tschopp, U. Obst-Sander, M. Kansy, K. Muller, and F. Diederich Fluorine interactions at the thrombin active site: protein backbone fragments H-C-alpha-CO comprise a favorable C-F environment and interactions of C-F with electrophiles ChemBioChem 5 2004 666 675
11. J.A. Olsen, D.W. Banner, P. Seiler, U.O. Sander, A. D'Arcy, M. Stihle, K. Muller, and F. Diederich A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: evidence for C-F⋯CO interactions Angew. Chem., Int. Ed. Engl. 42 2003 2507 2511
12. W.K. Hagmann The many roles for fluorine in medicinal chemistry J. Med. Chem. 51 2008 4359 4369
13. N.H. Hauel, H. Nar, H. Priepke, U. Ries, J.M. Stassen, and W. Wienen Structure-based design of novel potent nonpeptide thrombin inhibitors J. Med. Chem. 45 2002 1757 1766
14. T.A. Springer, J. Zhu, and T. Xiao Structural basis for distinctive recognition of fibrinogen gammaC peptide by the platelet integrin alphaIIbbeta3 J. Cell Biol. 182 2008 791 800
15. L. Lee, K.D. Kreutter, W. Pan, C. Crysler, J. Spurlino, M.R. Player, B. Tomczuk, and T. Lu 2-(2-Chloro-6-fluorophenyl)acetamides as potent thrombin inhibitors Bioorg. Med. Chem. Lett. 17 2007 6266 6269
16. E.A. Meyer, R.K. Castellano, and F. Diederich Interactions with aromatic rings in chemical and biological recognition Angew. Chem., Int. Ed. Engl. 42 2003 1210 1250
17. 50) of an enzymatic reaction Biochem. Pharmacol. 22 1973 3099 3108
18. E. Addicks, R. Mazitschek, and A. Giannis Synthesis and biological investigation of novel tricyclic benzodiazepinedione-based RGD analogues ChemBioChem 3 2002 1078 1088