Fluorinated benzyloxyphenyl piperidine-4-carboxamides with dual function against thrombosis: Inhibitors of factor xa and platelet aggregation

Journal of Medicinal Chemistry

Volumn 52, Issue 4, 2009, Pages 1018-1028

  De Candia, Modesto ^a   Liantonio, Francesco ^a   Carotti, Andrea ^a,b   De Cristofaro, Raimondo ^c   Altomare, Cosimo ^a  

^a UNIVERSITY OF BARI   (Italy)

^b CATHOLIC UNIVERSITY   (Italy)

^c UNIVERSITY OF PERUGIA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

1 [AMINO(IMINO)METHYL] N [3 [(4 FLUOROBENZYL)OXY]PHENYL]PIPERIDINE 4 CARBOXAMIDE HYDROCHLORIDE; AMIDE; ANTITHROMBOCYTIC AGENT; BLOOD CLOTTING FACTOR 10A; ISONIPECOTIC ACID; N [3 [(3' FLUORO 1,1' BIPHENYL 4 YL)METHOXY]PHENYL]PIPERIDINE 4 CARBOXAMIDE; N [3 [(4 FLUOROBENZYL)OXY]PHENYL]PIPERIDINE 3 CARBOXAMIDE HYDROCHLORIDE; N [[3 (1,1 BIPHENYL 4 YL)METHOXY]PHENYL]PIPERIDINE 4 CARBOXAMIDE HYDROCHLORIDE; NIPECOTIC ACID DERIVATIVE; PIPERIDINE; TERT BUTYL 4 [N (3 HYDROXYPHENYL)CARBAMOYL]PIPERIDINE 1 CARBOXYLATE; THROMBIN; UNCLASSIFIED DRUG;

ADULT; ARTICLE; BLOOD CLOTTING; CHEMICAL REACTION; DRUG ACTIVITY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; IN VITRO STUDY; LIPOPHILICITY; STRUCTURE ACTIVITY RELATION; THROMBOCYTE AGGREGATION; THROMBOSIS;

ADULT; ANILIDES; ANTICOAGULANTS; BLOOD PLATELETS; CELLS, CULTURED; FACTOR XA; HALOGENATION; HUMANS; MIDDLE AGED; PIPERIDINES; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBOSIS;

EID: 64349119325     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm801141f     Document Type: Article

References (63)

1. Mackman, N. Triggers, targets and treatment for thrombosis. Nature 2008, 451, 914-918.
2. (a) World Health Organization. Atlas of Heart Disease and Stroke; World Health Organization: Geneva, Switzerland, 2004.
3. (b) American Heart Association. Heart Disease and Stroke Statistics: 2008 Update; American Heart Association: Dallas, TX, 2008.
4. Meadows, T. A.; Bhatt, D. L. Clinical aspects of platelet inhibitors and thrombus formation. Circ. Res. 2007, 100, 1261-1275.
5. Gresele, P.; Agnelli, G. Novel approaches to the treatment of thrombosis. Trends Pharmacol. Sci. 2002, 23, 25-32.
6. Weitz, J. I.; Linkins, L. A. Beyond heparin and warfarin: the new generation of anticoagulants. Expert Opin. Invest. Drugs 2007, 16, 271-282.
7. Vacca, J. P. New advances in the discovery of thrombin and factor Xa inhibitors. Curr. Opin. Chem. Biol. 2000, 4, 394-400.
8. Stormoken, H. In Platelets Responses andMetabolism; Holmsen, H., Ed.; CRS Press: Boca Raton, FL, 1986; Vol. 3.
9. Fuster, V.; Badimon, L.; Badimon, J. J.; Chesebro, J. H. The pathogenesis of coronary artery disease and the acute coronary syndromes. N. Engl. J. Med. 1992, 326, 242-250.
10. Weksler, B. B. Antiplatelet agents in stroke prevention. Combination therapy: present and future. Cerebrovasc. Dis. 2000, 10 (Suppl. 5), 41-48.
11. Brass, L. Molecular basis for platelet activation. In Hematology: Basic Principles andPractice Hoffman, R., Benz, E. J., Shattil, S. J., Furie, B., Cohen, H. J., Silberstein, L. E., Eds.; Churchill Livingstone: New York, 1995; pp 1536-1552.
12. Gachet, C. The platelet P2 receptors as molecular targets for old and new antiplatelet drugs. Pharmacol. Ther. 2005, 108, 180-192.
13. Andronati, S. A.; Karaseva,T. L.;Krysko,A. A Peptidomimetics-Antagonists of the Fibrinogen Receptor: Molecular Design, Structures, Properties and Therapeutic Applications. Curr. Med. Chem. 2004, 11, 1183-1211.
14. Chackalamannil, S.; Wang, Y.; Greenlee, W. IJ.; Hu, Z.; Xia, Y.; Ahn, H.-S.; Boykow, G.; Hsieh, Y.; Palamanda, J.; Agans-Fantuzzi, J.; Kurowski, S.; Graziano, M.; Chintala, M. Discovery of a novel, orally active himbacine-based thombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J. Med. Chem. 2008, 51, 3061-3064.
15. Savi, P.; Herbert, G. M. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate antagonists for the prevention of atherothrombosis. Semin. Thromb. Hemostasis 2005, 31, 174-183.
16. Arepally, G. M.; Ortel, T. L. Heparin-induced trombocitopenia. N. Engl. J. Med. 2006, 355, 809-817.
17. Chan, Y. C.; Valenti, D.; Mansfield, A. O.; Stansby, G. Warfarin induced skin necrosis. Br. J. Surg. 2000, 87, 266-272.
18. Krynetskly, E. Building individualized medicine: prevention of adverse reactions to warfarin therapy. J. Pharmacol. Exp. Ther. 2007, 322, 427-434.
19. Hirsch, J. Current anticoagulant therapy-unmet clinical needs. Thromb. Res. 2003, 109,S1-S8.
20. Steinmettzer, T.; Stürzebecher, J. Progress in the development of synthetic thrombin inhibitors as new orally active anticoagulants. Curr. Med. Chem. 2004, 11, 2297-2321.
21. Gould, W. R. Recent advances in the discovery and development of direct coagulation Factor Xa inhibitors. Curr. Pharm. Des. 2003, 9, 2337-2347.
22. Hauel, N. H.; Nar, H.; Priepke, H.; Stassen, J.-M.; Wienen, W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J. Med. Chem. 2002, 45, 1757-1766.
23. Eriksson, B. I.; Dahl, O. E.; Rosencher, N.; Kurth, A. A.; van Dijk, C. N.; Frostick, S. P.; Prins, M. H.; Hettiarachchi, R.; Hantel, S.; Schnee, J.; Biiller, H. R. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, noninferiority trial. Lancet 2007, 370, 949-956.
24. Roherig, S.; Straub, A.; Pohlmann, J.; Lampe, T.; Pernerstorfer, J.; Schlemmer, K.-H.; Reinemer, P.; Perzborn, E. Discovery ofthe novel antithrombotic agent 5-chloro-N({(5S)-2-oxo-3-[4-(3-oxomorpholin- 4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiphene-2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J. Med. Chem. 2005, 48, 5900-5908.
25. Fisher, W. D.; Eriksson, B. I.; Bauer, K. A.; Borris, L.; Dahl, O. E.; Gent, M.; Haas, S.; Homering, M.; Huisman, M. V.; Kakkar, A. K.; Kalebo, P.; Kwong, L. M.; Misselwitz, F.; Turpie, A. G. Rivaroxaban for thromboprophylaxis after orthopaedic therapy: pooled analysis of two studies. Thromb. Haemostasis 2007, 97, 931-937.
26. (a) Quan, M. L.; Smallheer, J. M. The race to an orally active Factor Xa inhibitor: Recent advances. Curr. Opin. Drug Discovyery Dey. 2004, 7, 460-169.
27. (b) Linkins, L.-A.; Weitz, J. I. New Anticoagulant Therapy. Annu. Rev. Med. 2005, 56, 63-77.
28. Leadley, R. J. Coagulation factor Xa inhibition: biological background and rationale. Curr. Top. Med. Chem. 2001, 1, 151-159.
29. Eikelboom, J. W.; Hirsh, J. Combined antiplatelet and anticoagulant therapy: clinical benefits and risks. J. Thromb. Haemostasis 2007, 5 (Suppl. 1), 255-263.
30. Perez-Gomez, F.; Alegría, E.; Berjón, J.; Iriarte, J. A.; Zumalde, J.; Salvador, A. Comparative effects of antiplatelet anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation. A randomized multicenter study. J. Am. Coll. Cardiol. 2004, 44, 1557-1566.
31. Prandoni, P. Links between arterial and venous disease. J. Intern. Med. 2007, 262, 341-350.
32. Schneider, D. J.; Sobel, B. E. Conundrums in the combined use of anticoagulants and antiplatelet drugs. Circulation 2007, 116, 305-315.
33. Anderluh, P. S.; Anderluh, M.; Ilas, J.; Mravljak, J.; Dolenc, M. S.; Stegnar, M.; Kikelj, D. 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. 2005, 48, 3110-3113.
34. (a) Feng, Z.; Gollamudi, R.; Dillingham, E. O.; Bond, S. E.; Lyman, B. A.; Purcell, W. P.; Hill, R. J.; Korfmacher, W. A. Molecular determinants of the platelet aggregation inhibitory activity of carbam- oylpiperidines. J. Med. Chem. 1992, 35, 2952-2958.
35. (b) Zheng, X.; Salgia, S. R.; Thompson, W. B.; Dillingham, E. O.; Bond, S. E.; Feng, Z.; Prasad, K. R.; Gollamudi, R. Design and synthesis of piperidine- 3-carboxamides as human platelet aggregation inhibitors. J. Med. Chem. 1995, 38, 180-188.
36. (c) Guo, Z.; Zheng, X.; Thompson, W.; Dugdale, M.; Gollamudi, R. New carbamoylpiperidines as human platelet aggregation inhibitors. Bioorg. Med. Chem. 2000, 8, 1041-1058.
37. (a) de Candia, M.; Summo, L.; Carrieri, A.; Altomare, C.; Nardecchia, A.; Cellamare, S.; Carotti, A. Investigation of Platelet Aggregation Inhibitory Activity by Phenyl Amides and Esters of iperidinecarboxylic Acids. Bioorg. Med. Chem. 2003, 11, 1439-1450.
38. (b) De Marco, A.; de Candia, M.; Carotti, A.; Cellamare, S.; De Candia, E.; Altomare, C. Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides. Eur. J. Pharm. Sci. 2004, 22, 153-164.
39. McMartin, C.; Bohacek, R. S. QXP: powerful, rapid computer algorithms for structure-based drug design. J. Comput.-Aided Mol. Des. 1997, 11, 333-344.
40. Adler, M.; Davey, D. D.; Phillips, G. B.; Kim, S. H.; Jancarik, J.; Rumennik, G.; Light, D. R.; Whitlow, M. Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa. Biochemistry 2000, 39, 12534-12542.
41. Warren, L. The PyMOL Molecular Graphics System; DeLano Scientific LLC, San Carlos, CA; http://www.pymol.org.
42. Lee, Y.-K.; Parks, D. J.; Lu, T.; Thieu, T. V.; Markotan, T.; Pan, W.; McComsey, D. F.; Milkiewicz, K. L.; Crysler, C. S.; Ninan, N.; Abad, M. C.; Giardino, E. C.; Maryanoff, B. E.; Damiano, B. P.; Player, M. R. 7-Fluoroindazoles as potent and selective inhibitors of factor Xa. J. Med. Chem. 2008, 51, 282-297.
43. Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst-Sander, U.; D'Arcy, A.; Stihle, M.; Muller, K.; Diederich, F. A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: Evidence for C-F⋯ C=O interactions. Angew. Chem., Int. Ed. 2003, 42, 2507-2511.
44. Mitsunobu, O. The Use of Diethyl Azodicarboxylate and Triph- enylphosphine in Synthesis and Transfromation of Natural Products. Synthesis 1981, 1-28.
45. Yuste, F.; Saldana, M. Selective reduction of nitrocompounds containing O-benzyl groups with hydrazine and Raney nickel without debenzylation. Tetrahedron Lett. 1982, 23, 147-148.
46. (a) Tromp, R. A.; van Ameijde, S.; Puetz, C.; Sundermann, C.; Sundermann, B.; von Kuenzel, J. K.; IJzerman, A. P. Inhibition of Nucleoside Transport by New Analogues of 4-Nitrobenzylthioinosine: Replacement of the Ribose Moiety by Substituted Benzyl Groups. J. Med. Chem. 2004, 47, 5441-5450.
47. (b) Robinson, R. P.; Laird, E. R.; Donahue, K. M.; Lopresti-Morrow, L. L.; Mitchell, P. G.; Reese, M. R.; Reeves, L. M.; Rouch, A. I.; Stam, E. J.; Yocum, S. A. Design and synthesis of 2-oxo-imidazolidine-4-carboxylic acid hydroxyamides as potent matrix metalloproteinase-13 inhibitors. Bioorg. Med. Chem. Lett. 2001, 11, 1211-1213.
48. (c) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. Catalytic Intermolecular Direct Arylation of Perfluorobenzenes. J. Am. Chem. Soc. 2006, 128, 8754-8756.
49. (d) Yamasaki, N.; Imoto, T.; Muray, Y.; Hiramura, T.; Oku, T.; Sawada, K. Preparation of benzimidazole derivatives as drugs. Patent WO 9724334, 1997.
50. Stanforth, S. P. Catalytic cross-coupling reactions in biaryl synthesis. Tetrahedron 1998, 54, 263-303.
51. Born, G. V. R. Aggregation of blood platelets by adenosine diphosphate (ADP) and its reversal. Nature 1962, 194, 927-929.
52. de Candia, M.; Fossa, P.; Cellamare, S.; Mosti, L.; Carotti, A.; Altomare, C. Insights into structure-activity relationships from lipophilicity profiles of pyridin-2(1H)-one analogs of the cardiotonic agent milrinone. Eur. J. Pharm. Sci. 2005, 26, 78-86.
53. Kooijman, E.; Tieleman, D. P.; Testerink, C.; Munnik, T.; Rijkers, D. T. S.; Burger, K. N. J.; de Kruijff, B. An electrostatic/hydrogen bond switch as the basis for specific interaction of phosphatidic acid with proteins. J. Biol. Chem. 2007, 282, 11356-11364.
54. Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. Fluorine in medicinal chemistry. ChemBioChem 2004, 5, 637-643.
55. Razgulin, A. V.; Mecozzi, S. Binding properties of aromatic carbon- bound fluorine. J. Med. Chem. 2006, 49, 7902-7906.
56. Olsen, J. A.; Banner, D. W.; Seiler, P.; Wagner, B.; Tschopp, T.; Obst-Sander, U.; Kansy, M.; Müller, K.; Diederich, F. Fluorine interactions at the thrombin active site: protein backbone fragments H-CαC=O comprise a favorable C-F environment and interactions of C-F with electrophiles. ChemBioChem 2004, 5, 666-675.
57. Kürschner, M.; Nielsen, K.; von Langen, J. R. G.; Schenk, W. A.; Zimmermann, U.; Sukhorukov, V. L. Effect of fluorine substitution on the interaction of lipophilic ions with the plasma membrane of mammalian cells. Biophys. J. 2000, 79, 1490-1497.
58. Akao, A.; Sato, K.; Nonoyama, N.; Masea, T.; Yasuda, N. Highly chemoselective reduction using a Rh/C- Fe(OAc)2 system: practical synthesis of functionalized indoles. Tetrahedron Lett. 2006, 47, 969-972.
59. Leban, J.; Kralik, M.; Mies, J.; Gassen, M.; Tentschert, K.; Baum- gartner, R. SAR, species specificity, and cellular activity of cyclo- pentene dicarboxylic acid amides as DHODH inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 4854-4857.
60. Shah, S. T. A.; Khan, K. M.; Hussain, H.; Anwar, M. U.; Feckera, M.; Voelter, W. Cesium fluoride-celite: a solid base for efficient syntheses of aromatic esters and ethers. Tetrahedron 2005, 61, 6652-6656.
61. Ueno, H.; Yokota, K.; Hoshi, J.; Yasue, K.; Hayashi, M.; Hase, Y.; Uchida, I.; Aisaka, K.; Katoh, S.; Cho, H. Synthesis and structure- activity relationships of novel selective factor Xa inhibitors with a tetrahydroisoquinoline ring. J. Med. Chem. 2005, 48, 3586-3604.
62. 50) of an enzymatic reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.
63. Bio-Loom for Windows, version 1.5; BioByte Corporation: Claremont, CA.