Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors

Journal of Medicinal Chemistry

Volumn 57, Issue 3, 2014, Pages 955-969

  Quan, Mimi L ^a   Wong, Pancras C ^a   Wang, Cailan ^a   Woerner, Francis ^a   Smallheer, Joanne M ^a   Barbera, Frank A ^a   Bozarth, Jeffrey M ^a   Brown, Randi L ^a   Harpel, Mark R ^a   Luettgen, Joseph M ^a   Morin, Paul E ^a   Peterson, Tara ^a   Ramamurthy, Vidhyashankar ^a   Rendina, Alan R ^a   Rossi, Karen A ^a   Watson, Carol A ^a   Wei, Anzhi ^a   Zhang, Ge ^a   Seiffert, Dietmar ^a   Wexler, Ruth R ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMALS; BLEEDING TIME; CRYSTALLOGRAPHY, X-RAY; FACTOR XA; FIBRINOLYTIC AGENTS; HUMANS; MOLECULAR CONFORMATION; MOLECULAR DOCKING SIMULATION; QUINOLINES; RABBITS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84894026200     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401670x     Document Type: Article

References (57)

1. Jackson, S. P. Nat. Med. 2011, 17, 1423-1436
2. Global Status Report on Noncommunicable Diseases 2010. WHO Press: Geneva, Switzerland, 2011.
3. WHO Fact Sheet No.310; WHO: Geneva, Switzerland, June 2011.
4. Ansell, J.; Hirsh, J.; Hylek, E.; Jacobson, A.; Crowther, M.; Palareti, G. The Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-based Clinical Practice Guidelines (8th edition) Chest 2008, 133, 160S-198S
5. Stein, P. D.; Grandison, D.; Hua, T. A. Therapeutic level of anticoagulation with warfarin in patients with mechanical prosthetic heart valves: review of literature and recommendations based on internal normalized ratio Postgrad. Med. J. 1994, 70 (Suppl. 1) S72-S83
6. Hirsh, J.; Poller, L. The international normalized ratio. A guide to understanding and correcting its problems Arch. Intern. Med. 1994, 154, 282-288
7. Yeh, C. H.; Fredenburgh, J. C.; Weitz, J. I. Oral direct factor Xa inhibitors Circ. Res. 2012, 111 (8) 1069-1078
8. Straub, A.; Roehrig, S.; Hillisch, A. Oral, direct thrombin and factor Xa inhibitors: the replacement for warfarin, leeches, and pig intestines Angew. Chem., Int. Ed. 2011, 50, 4574-4591
9. Blommel, M. L.; Blommel, A. L. Dabigatran etexilate: a novel oral direct thrombin inhibitor Am. J. Health-Syst. Pharm. 2011, 68 (16) 1506-1519
10. Pinto, D. J. P.; Smallheer, J. M.; Cheney, D. L.; Knabb, R. M.; Wexler, R. R. Factor Xa inhibitors: next-generation antithrombotic agents J. Med. Chem. 2010, 53 (17) 6243-6274
11. Haas, S. New oral Xa and IIa inhibitors: updates on clinical trial results J. Thromb. Thrombolysis 2008, 25, 52-60
12. Spinler, S. The pharmacology and therapeutic use of dabigatran etexilate J. Clin. Pharmacol. 2013, 53 (1) 1-13
13. King, C. S.; Holley, A. B.; Moores, L. K. Moving toward a more ideal anticoagulant: the oral direct thrombin and factor Xa inhibitors Chest J. 2013, 143 (4) 1106-1116
14. Thomas, T. F.; Ganetsky, V.; Spinler, S. A. Rivaroxaban, an oral factor Xa inhibitor Clin. Ther. 2013, 35 (1) 4-27
15. Misselwitz, F.; Berkowwitz, S. D.; Perzborn, E. The discovery and development of rivaroxaban Ann. N.Y. Acad. Sci. 2011, 1222, 64-75
16. Piccini, J.; Patel, M.; Mahaffey, K. W.; Fox, K. A.; Califf, R. M. Rivaroxaban, an oral direct factor Xa inhibitor Expert. Opin. Invest. Drugs 2008, 17, 925-937
17. Pinto, D. J. P.; Wong, P. C.; Knabb, R. M.; Wexler, R. R. Case history: Eliquis (apixaban), a potent and selective inhibitor of coagulation factor Xa for the prevention and treatment of thrombotic diseases Annu. Rep. Med. Chem. 2012, 47, 123-139
18. Pinto, D. J. P.; Orwat, M. J.; Koch, S.; Rossi, K. A.; Alexander, R. S.; Smallwood, A.; Wong, P. C.; Rendina, A. R.; Luettgen, J. M.; Knabb, R. M.; He, K.; Xin, B.; Wexler, R. R.; Lam, P. Y. S. The discovery of 1-(4-methoxyphenyl)- 7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious and orally bioavailable inhibitor of blood coagulation factor Xa J. Med. Chem. 2007, 50, 5339-5356
19. He, K.; Luettgen, J. M.; He, B.; Grace, J. E., Jr.; Zhang, D.; Xin, B.; Pinto, D. J.; Wong, P. C.; Knabb, R. M.; Lam, P. S. Y.; Wexler, R. R.; Grossman, S. J. Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor Eur. J. Drug Metab. Pharmacokinet. 2011, 36 (3) 129-139
20. Luettgen, J. M.; Knabb, R. M.; He, K.; Pinto, D. J.; Rendina, A. R. Apixaban inhibition of factor Xa: microscopic rate constants and inhibition mechanism in purified protein systems and in human plasma J. Enzyme Inhib. Med. Chem. 2011, 26 (4) 514-26
21. Lassen, M. R.; Davidson, B. L.; Gallus, A.; Pineo, G.; Ansell, J.; Deitchman, D. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement J. Thromb. Haemostasis 2007, 5, 2368-2375
22. Wong, P. C.; Crain, E. J.; Xin, B.; Wexler, R. R.; Lam, P. Y. S.; Pinto, D. J.; Luettgen, J. M.; Knabb, R. M. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies J. Thromb. Haemostasis 2008, 6, 820-829
23. Granger, C. B.; Alexander, J. H.; McMurray, J. J.; Lopes, R. D.; Hylek, E. M.; Hanna, M.; Al-Khalidi, H. R.; Ansell, J.; Atar, D.; Avezum, A.; Bahit, M. C.; Diaz, R.; Easton, J. D.; Ezekowitz, J. A.; Flaker, G.; Garcia, D.; Geraldes, M.; Gersh, B. J.; Golitsyn, S.; Goto, S.; Hermosillo, A. G.; Hohnloser, S. H.; Horowitz, J.; Mohan, P.; Jansky, P.; Lewis, B. S.; Lopez-Sendon, J. L.; Pais, P.; Parkhomenko, A.; Verheugt, F. W.; Zhu, J.; Wallentin, L. Apixaban versus warfarin in patients with atrial fibrillation N. Engl. J. Med. 2011, 365 (11) 981-992
24. Schenone, M.; Furie, B. C.; Furie, B. The blood coagulation cascade Curr. Opin. Hematol. 2004, 11 (4) 272-277
25. Gailani, D.; Renné, T. Intrinsic pathway of coagulation and arterial thrombosis Arterioscler., Thromb., Vasc. Biol. 2007, 27, 2507-2513
26. Gailani, D.; Renné, T. Intrinsic pathway of coagulation and arterial thrombosis Arterioscler., Thromb., Vasc. Biol. 2007, 27, 2507-2513
27. Gailani, D.; Renné, T. The intrinsic pathway of coagulation: a target for treating thromboembolic disease? J. Thromb. Haemostasis 2007, 5, 1106-1112
28. Schumacher, W.; Luettgen, J.; Quan, M. L.; Seiffert, D. Inhibition of factor XIa as a new approach to anticoagulant Arterioscler., Thromb., Vasc. Biol. 2010, 30, 388-392
29. Emsley, J.; McEwan, P. A.; Gailani, D. Structure and function of factor XI Blood 2010, 115 (13) 2569-2577
30. Seligsohn, U. Factor XI in haemostasis and thrombosis: past, present and future Thromb. Haemostasis 2007, 98, 84-89
31. Franchini, M.; Veneri, D.; Lippi, G. Inherited factor XIa deficiency: a concise review Hematology 2006, 11, 307-309
32. Gailani, D.; Lasky, N.; Broze, G. A murine model of factor XI deficiency Blood Coagulation Fibrinolysis 1997, 8, 134-144
33. Wang, X.; Cheng, I.; Xu, I.; Feuerstein, G. Z.; Hsu, M.-Y.; Smith, P. L.; Seiffert, D.; Schumacher, W. A.; Ogletree, M. L.; Gailani, D. J. Thromb. Haemostasis 2005, 3, 695-702
34. 3-induced injury of the carotid artery in the mouse Thromb. Haemostasis 2002, 87, 774-777
35. Reviewed in the following: Camire, R. M.; Pollak, E. S. Genetics of Coagulation. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 5 th ed.; Colman, R. W.; Marder, V. J.; Clowes, A. W.; George, J. N.; Goldhaber, S. Z., Eds.; Lippincott Williams & Wilkins: Philadephia, PA, 2006; pp 59-89.
36. Yang, D. T.; Flanders, M. M.; Kim, H.; Rodgers, G. M. Elevated factor XIa activity levels are associated with an increased odds ratio for cerebrovascular events Am. J. Clin. Pathol. 2006, 126, 411-415
37. Butenas, S.; Undas, A.; Gissel, M. T.; Szuldrzynski, K.; Zmudka, K.; Mann, K. G. Factor XIa and tissue factor activity in patients with coronary artery disease Thomb. Haemostasis 2008, 99, 142-149
38. Salomon, O.; Steinberg, D. M.; Koren-Morag, N.; Tanne, D.; Seligsohn, U. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency Blood 2008, 111, 4113-4117
39. Lazarova, T. I.; Jin, L.; Rynkiewicz, M. J.; Gorga, J. C.; Bibbins, F.; Meyers, H. V.; Babine, R.; Strickler, E. J. Synthesis and in vitro biological evaluation of aryl boronic acids as potential inhibitors of factor XIa Bioorg. Med. Chem. Lett. 2006, 16, 5022-5027
40. Buchanan, M. S.; Carroll, A. R.; Wessling, D.; Jobling, M.; Avery, V. M.; Davis, R. A.; Feng, Y.; Xue, Y.; Oster, L.; Fex, T.; Deinum, J.; Hooper, J. N. A.; Quinn, R. J. Clavatadine A, a natural product with selective recognition and irreversible inhibition of factor XIa J. Med. Chem. 2008, 51, 3583-3587
41. Deng, H.; Bannister, T. D.; Jin, L.; Babine, R. E.; Quinn, J.; Nagafuji, P.; Celatka, C. A.; Lin, J.; Lazarova, T. I.; Rynkiewice, M. J.; Bibbins, F.; Pandey, P.; Gotga, J.; Meyers, H. V.; Abdel-Meguid, S. S.; Strickler, J. E. Synthesis, SAR exploration, and X-ray crystal structures of factor XIa inhibitors containing an α-ketothiazole arginine Bioorg. Med. Chem. Lett. 2006, 16, 3049-3054
42. Lin, J.; Deng, H.; Pabdey, P.; Quinn, J.; Cantin, S.; Rynkiewicz, M. J.; Gorga, J. C.; Bibbins, F.; Celatka, C. A.; Nagafuji, P.; Bannister, T. D.; Meyers, H. V.; Babine, R.; Hayward, N. J.; Weaver, D.; Benjamin, H.; Stassen, F.; Abdel-Meguid, S. S.; Strickler, E. J. Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants J. Med. Chem. 2006, 49, 7781-7791
43. Wong, P. C.; Crain, E. J.; Watson, C. A.; Schumacher, W. A. A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits J. Thromb. Thrombolysis 2011, 32 (2) 129-137
44. Schumacher, W. A.; Seiler, S. E.; Steinbacher, T. E.; Stewart, A. B.; Bostwick, J. B.; Hartl, K. S.; Liu, E. C.; Ogletree, M. L. Antithrombotic and hemostatic effects of a small molecule factor XIa inhibitor in rats Eur. J. Pharmacol. 2007, 570, 167-174
45. A portion of this work was presented at the following: Quan, M. L. Tetrahydroquinoline Derivatives as Potent and Selective Factor XIa Inhibitors. Presented at the 22nd International Symposium on Medicinal Chemistry, Berlin, Germany, September 2-6, 2012; Abstract L63.
46. Priestley, E. S.; DeLucca, I.; Zhou, J.; Saiah, E.; Stanton, R.; Robinson, L.; Luettgen, J. M.; Wei, A.; Wen, X.; Knabb, R. M.; Wong, P. C.; Wexler, R. R. Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor Bioorg. Med. Chem. Lett. 2013, 23, 2432-2435
47. DeLucca, I.; Zhou, J.; Saiah, E.; Mersinger, L.; Kettner, C.; Wei, A.; Wen, X.; Crain, E.; Watson, C.; Wong, P. C.; Wexler, R. R.; Priestley, E. S. A Selective FVIIa Inhibitor with Efficacy in an Arterial Thrombosis Model. Abstracts of Papers, 30th National Meeting of the American Chemical Society, August, 2005; American Chemical Society: Washington, DC, 2005; MEDI-2832.
48. Wong, P. C.; Luettgen, J. M.; Rendina, A. R.; Kettner, C. A.; Xin, B.; Knabb, R. M.; Wexler, R. R.; Priestley, E. S. BMS-593214, an active site-directed factor VIIa inhibitor: enzyme kinetics, antithrombotic and antihaemostatic studies Thromb. Haemostasis 2010, 104, 261-269
49. Pedicord, D. L.; Seiffert, D.; Blat, Y. Substrate-dependent modulation of the mechanism of factor XIa inhibition Biochemistry 2004, 43 (37) 11883-11888
50. Wong, P. C.; Quan, M. L.; Watson, C.; Crain, E.; Wexler, R. R.; Knabb, R. M. Nonpeptide factor Xa inhibitors: I. Studies with SF303 and SK549, a new class of potent antithrombotics J. Pharmacol. Exp. Ther. 2000, 292, 351-357
51. Wong, P. C.; Quan, M. L.; Watson, C.; Crain, E.; Wexler, R. R.; Seiffert, D. Potent Antithrombotic Effect of a Small-Molecule, Reversible and Direct Inhibitor of Factor XIa with Minimum Bleeding Time Effect in Rabbit Models of Arterial Thrombosis and Hemostasis. Presented at the American Heart Association Meeting, Nov 2013; APS.709.03, Poster 7050.
52. Miura, M.; Seki, N.; Ishihara, T.; Niimi, T.; Hirayama, F.; Shigenaga, T.; Sakai-Moritani, Y.; Kawasaki, T.; Sakamoto, S.; Okada, M.; Ohta, M.; Tsukamoto, S. Potent and selective TF/FVIIa inhibitors containing a neutral P1 ligand Bioorg. Med. Chem. 2006, 14, 7688-7705
53. Otwinowski, Z.; Minor, W. Macromolecular Crystallography. Part A; Carter, C. W., Jr.; Sweet, R. M., Eds.; Methods in Enzymology, Vol. 276; Academic Press: New York, NY; 1997; pp 307-326.
54. Blanc, E.; Roversi, P.; Vonrhein, C.; Flensburg, C.; Lea, S. M.; Bricogne, G. Refinement of severely incomplete structures with maximum likelihood in BUSTER/TNT Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60, 2210-2221
55. Emsley, P.; Lokhamp, B.; Scott, W. G.; Cowtan, K. Features and evelopment of Coot Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 486-501
56. Miletich, J. P.; Broze, G. J., Jr.; Majerus, P. W. Purification of human coagulation factors II, IX, and X using sulfated dextran beads Methods Enzymol. 1981, 80, 221-228
57. De La Cadena, R. A.; Scott, C. F.; Colman, R. W. Evaluation of a microassay for human plasma prekallikrein J. Lab. Clin. Med. 1987, 109 (5) 601-607