Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity

Journal of Medicinal Chemistry

Volumn 57, Issue 23, 2014, Pages 9915-9932

  Hangeland, Jon J ^a   Friends, Todd J ^a   Rossi, Karen A ^a   Smallheer, Joanne M ^a   Wang, Cailan ^a   Sun, Zhong ^a   Corte, James R ^a   Fang, Tianan ^a   Wong, Pancras C ^a   Rendina, Alan R ^a   Barbera, Frank A ^a   Bozarth, Jeffrey M ^a   Luettgen, Joseph M ^a   Watson, Carol A ^a   Zhang, Ge ^a   Wei, Anzhi ^a   Ramamurthy, Vidhyashankar ^a   Morin, Paul E ^a   Bisacchi, Gregory S ^a   Subramaniam, Srinath ^a   Arunachalam, Piramanayagam ^a   Mathur, Arvind ^a   Seiffert, Dietmar A ^a   Wexler, Ruth R ^a   Quan, Mimi L ^a   more..

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [4 [2 [1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL]PHENYL]ACETIC ACID, BIS TRIFLUOROACETIC ACID SALT; 2 [4 [2 [1 [TRANS 4 [(TERT BUTOXYCARBONYLAMINO)METHYL]CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL]PHENYL]ACETIC ACID; 3 [2 [1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL]BENZAMIDE, BIS TRIFLUOROACETIC ACID SALT; 4 [2 ([1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 5 BROMO 1H IMIDAZOL 4 YL] BENZAMIDE, BIS TRIFLUOROACETIC ACID SALT; 4 [2 [1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL] N METHYLBENZAMIDE, BIS TRIFLUOROACETIC ACID SALT; 4 [2 [1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL] N,N DIMETHYLBENZAMIDE, BIS TRIFLUOROACETIC ACID SALT; 4 [2 [1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL]BENZAMIDE, BIS TRIFLUOROACETIC ACID SALT; 4 [2 [1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL]BENZOIC ACID, BIS TRIFLUOROACETIC ACID SALT; 4 [2 [1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 5 CHLORO 1H IMIDAZOL 4 YL] BENZAMIDE, BIS TRIFLUOROACETIC ACID SALT; 4 [2 [1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 5 FLUORO 1H IMIDAZOL 4 YL] BENZAMIDE, BIS TRIFLUOROACETIC ACID SALT; 4 [2 [1 [TRANS 4 [(TERT BUTOXYCARBONYLAMINO)METHYL]CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL] BENZOIC ACID; ANTICOAGULANT AGENT; BLOOD CLOTTING INHIBITOR; ETHYL 2 [3 [2 [1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL]PHENYL]ACETATE, BIS TRIFLUOROACETIC ACID SALT; ETHYL 2 [4 [2 [1 [TRANS 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL]PHENYL] ACETATE, BIS TRIFLUOROACETIC ACID SALT; IMIDAZOLE DERIVATIVE; METHYL 4 [2 [1 [TRANS 4 (AMINOMETHYL) CYCLOHEXANECARBOXAMIDO] 2 PHENYLETHYL] 1H IMIDAZOL 4 YL] BENZOATE, BIS TRIFLUOROACETIC ACID SALT; PHENYLIMIDAZOLE DERIVATIVE; TERT BUTYL [2 PHENYL 1 (4 PHENYL 1H IMIDAZOL 2 YL)ETHYL]CARBAMATE; TERT BUTYL [TRANS 4 [[1 [4 [4 (2 AMINO 2 OXOETHYL)PHENYL] 1H IMIDAZOL 2 YL] 2 PHENYLETHYL]CARBAMOYL]CYCLOHEXYL]CARBAMATE; TERT BUTYL [[TRANS 4 [[1 [4 (4 CARBAMOYLPHENYL) 1H IMIDAZOL 2 YL] 2 PHENYLETHYL]CARBAMOYL]CYCLOHEXYL]METHYL]CARBAMATE; TERT BUTYL [[TRANS 4 [[1 [4 [4 (METHYLCARBAMOYL)PHENYL] 1H IMIDAZOL 2 YL] 2 PHENYLETHYL]CARBAMOYL]CYCLOHEXYL] METHYL]CARBAMATE; TERT BUTYL [[TRANS 4 [[1 [5 BROMO 4 (4 CARBAMOYLPHENYL) 1H IMIDAZOL 2 YL] 2 PHENYLETHYL]CARBAMOYL]CYCLOHEXYL]METHYL)CARBAMATE; TERT BUTYL [[TRANS 4 [[2 PHENYL 1 (4 PHENYL 1H IMIDAZOL 2 YL)ETHYL]CARBAMOYL]CYCLOHEXYL]METHYL]CARBAMATE; TRANS 4 (AMINOMETHYL) N [1 [4 (3 CYANOPHENYL) 1H IMIDAZOL 2 YL] 2 PHENYLETHYL]CYCLOHEXANECARBOXAMIDE, BIS TRIFLUOROACETIC ACID SALT; TRANS 4 (AMINOMETHYL) N [1 [4 (4 CYANOPHENYL) 1H IMIDAZOL 2 YL] 2 PHENYLETHYL]CYCLOHEXANECARBOXAMIDE, BIS TRIFLUOROACETIC ACID SALT; TRANS 4 (AMINOMETHYL) N [2 PHENYL 1 (4 PHENYL 1H IMIDAZOL 2 YL)ETHYL]CYCLOHEXANECARBOXAMIDE, BIS TRIFLUOROACETIC ACID SALT; TRANS 4 (AMINOMETHYL) N [2 PHENYL 1 [4 (4 SULFAMOYLPHENYL) 1H IMIDAZOL 2 YL]ETHYL]CYCLOHEXANECARBOXAMIDE, BIS TRIFLUOROACETIC ACID SALT; TRANS N [1 [4 [4 (2 AMINO 2 OXOETHYL)PHENYL] 1H IMIDAZOL 2 YL] 2 PHENYLETHYL] 4 (AMINOMETHYL)CYCLOHEXANECARBOXAMIDE, BIS TRIFLUOROACETIC ACID SALT; UNCLASSIFIED DRUG; UNINDEXED DRUG; FIBRINOLYTIC AGENT; INDAZOLE DERIVATIVE; TRANS-N-((S)-1-(4-(3-AMINO-1H-INDAZOL-6-YL)-5-CHLORO-1H-IMIDAZOL-2-YL)-2-PHENYLETHYL)-4-(AMINOMETHYL)CYCLOHEXANECARBOXAMIDE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTICOAGULATION; ARTERIOVENOUS SHUNT THROMBOSIS; ARTICLE; BLOOD CLOTTING; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BLOOD LEVEL; DRUG POTENCY; DRUG SYNTHESIS; ENANTIOMER; ENZYME INHIBITION; EXPERIMENTAL RABBIT; HYDROGEN BOND; IN VITRO STUDY; IN VIVO STUDY; LOADING DRUG DOSE; MOLECULAR MODEL; MOUSE; NONHUMAN; VEIN THROMBOSIS; VOLUME OF DISTRIBUTION; ANIMAL; CHEMICAL STRUCTURE; HUMAN; PARTIAL THROMBOPLASTIN TIME; RABBIT; SYNTHESIS; THROMBOSIS; X RAY CRYSTALLOGRAPHY;

ANIMALS; CRYSTALLOGRAPHY, X-RAY; FIBRINOLYTIC AGENTS; HUMANS; IMIDAZOLES; INDAZOLES; MODELS, MOLECULAR; PARTIAL THROMBOPLASTIN TIME; RABBITS; THROMBOSIS;

EID: 84918566382     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm5010607     Document Type: Article

References (45)

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. World Health Organization: Geneva, Switzerland, June 2011.
4. Mcfarlane, R. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier Nature 1964, 202, 498-499
5. Davie, E. W.; Ratnoff, O. Waterfall sequence for intrinsic clotting Science 1964, 145, 1310-1313
6. Davie, E. W.; Fujikawa, K.; Kisiel, W. The coagulation cascade: initiation, maintenance and regulation Biochemistry 1991, 30, 10363-10370
7. Gailani, D.; Broze, G. Factor XI activation in a revised model of blood coagulation Science 1991, 253, 909-912
8. Müller, F.; Mutch, N. J.; Schenk, W. A.; Smith, S. A.; Esterl, L.; Spronk, H. M.; Schmidbauer, S.; Gahl, W. A.; Morrissey, J. H.; Renné, T. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo Cell 2009, 139, 1143-1156
9. Chatterjee, K.; Guo, Z.; Vogler, E. A.; Siedlecki, C. A. Contributions of contact activation pathways of coagulation factor XII in plasma J. Biomed. Mater. Res. 2009, 90A, 27-34
10. Asakai, R.; Chung, D.; Davie, E.; Seligsohn, U. Factor XI deficiency in Ashkenazi Jews in Israel N. Engl. J. Med. 1991, 325, 153-158
11. Gailani, D.; Broze, G. J. Factor XI and the Contact System. In The Metabolic and Molecular Basis of Inherited Disease, 8 th ed.; Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D.; Childs, B.; Kinzler, K. W.; Vogelstein, B., Eds.; McGraw-Hill: New York, 2001; p 4433.
12. Gailani, D.; Renné, T. The intrinsic pathway for coagulation: A target for treating thromboembolic disease? J. Thromb. Haemostasis 2007, 5, 1106-1112
13. 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
14. Bolton-Maggs, P. H.; Patterson, D. A.; Wensley, R. T.; Tuddenham, E. G. Definition of the bleeding tendency in factor XI-deficient kindreds-a clinical and laboratory study Thromb. Haemostasis 1995, 73, 194-202
15. Lozier, J. N.; Kessler, C. M. Clinical Aspects and Therapy of Hemophilia. In Hematology: Basic Principles and Practice, 4 th ed.; Hoffman, R.; Benz, E.; Shattil, S.; Furie, B.; Cohen, H.; Silberstein, L.; McGlave, P., Eds.; Churchill Livingstone: New York, 2005; p 2047.
16. Wang, X.; Smith, P. L.; Hsu, M.-Y.; Gailani, D.; Schumacher, W. A.; Ogletree, M. L.; Seiffert, D. A. Effects of factor XI deficiency on ferric chloride-induced vena cava thrombosis in mice J. Thromb. Haemostasis 2006, 4, 1982-1988
17. 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
18. 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
19. 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
20. Lin, J.; Deng, H.; Jin, L.; Pandey, 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. E.; Hayward, N. J.; Weaver, D.; Benjamin, H.; Stassen, F.; Abdel-Meguid, S. S.; Strickler, J. E. Design, Synthesis, and Biological Evaluation of Peptidimimetic Inhibitors of Factor XIa as Novel Anticoagulants J. Med. Chem. 2006, 49, 7781-7791
21. 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
22. 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
23. 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, 129-137
24. Sutton, J. C.; Bolton, S. A.; Hartl, K. S.; Huang, M.-H.; Jacobs, G.; Meng, W.; Ogletree, M. L.; Pi, Z.; Schumacher, W. A.; Seiler, S. M.; Slusarchyk, W. A.; Treuner, U.; Zhaler, R.; Zhao, G.; Basicchi, G. S. Synthesis and SAR of 4-carboxy-2-azetidinone mechanism-based tryptase inhibitors Bioorg. Med. Chem. Lett. 2002, 12, 3229-3233
25. Quan, M. L.; Wong, P. C.; Wang, C.; Woerner, F.; Smallheer, J. M.; Barbera, F. A.; Bozarth, J. M.; Brown, R. L.; Harpel, M. R.; Luettgen, J. M.; Morin, P. E.; Peterson, T.; Ramamurthy, V.; Rendina, A. R.; Rossi, K. A.; Watson, C. A.; Wei, A.; Zhang, G.; Seiffert, D.; Wexler, R. R. J. Med. Chem. 2014, 57, 955-969
26. 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 Scientific Sessions, November 2013; APS.709.03, Poster 7050.
27. Buchanan, M. S.; Carroll, A. R.; Wessling, D.; Jobling, M.; Avery, V. M.; Davis, R. A.; Feng, Y.; Zue, Y.; 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
28. Lazarova, T. I.; Jin, L.; Rynkiewicz, M.; Gorga, J. C.; Bibbins, F.; Meyers, H. V.; Babine, R.; Strickler, J. Synthesis and in vitro biological evaluation or aryl boronic acids as potential inhibitors of factor XIa Bioorg. Med. Chem. Lett. 2006, 16, 5022-5027
29. Smallheer, J. M.; Wang, S.; Rossi, K. A.; Rendina, A.; Morin, P. E.; Wei, A.; Zhang, G.; Wong, P. C.; Seiffert, D.; Wexler, R. R.; Quan, M. L. Abstracts of Papers, 245th National Meeting of the American Chemical Society, New Orleans, LA, U.S., April 7-11, 2013; American Chemical Society: Washington, DC, 2013; MEDI-415.
30. Sinha, D.; Badellina, K. O.; Marcinkiewicz, M.; Walsh, P. N. Allosteric modification of factor XIa functional activity upon binding to polyanions Biochemistry 2004, 43, 7593-7600
31. Argade, M. D.; Mehta, A. Y.; Sarkar, A.; Desai, U. R. Allosteric inhibition of human factor XIa: discovery of monosulfated benzofurans as a class of promising inhibitors J. Med. Chem. 2014, 57, 3559-3569
32. Al-Horani, R. A.; Desai, U. R. Designing allosteric inhibitors of factor XIa. Lessons from the interactions of sulfated pentagalloylglucopyranosides J. Med. Chem. 2014, 57, 4805-4818
33. Al-Horani, R. A.; Ponnusamy, P.; Mehta, A. Y.; Gailani, D.; Desai, U. R. Sulfated pentagalloylglucoside is a potent, allosteric, and selective inhibitor of factor XIa J. Med. Chem. 2013, 56, 867-878
34. Karuturi, R.; Al-Horani, R. A.; Mehta, S. C.; Gailani, D.; Desai, U. R. Discovery of allosteric modulators of factor XIa by targeting the hydrophobic domains adjacent to its heparin-binding site J. Med. Chem. 2013, 56, 2415-2428
35. Ma, D.; Mizurini, D. M.; Assumpcao, T. C. F.; Li, Y.; Qi, Y.; Kotsyfakis, M.; Ribeiro, J. M. C.; Monteiro, R. Q.; Francischetti, I. M. B. Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo Blood 2013, 122, 4094-4106
36. Wong, P. C.; Quan, M. L.; Crain, E. J.; Watson, C. A.; Wexler, R. R.; Knabb, R. M. Nonpeptide factor Xa inhibitors: studies with SF303 and SK549, a new class of potent antithrombotics J. Pharmacol. Exp. Ther. 2000, 292, 351-357
37. Wong, P. C.; Crain, E. J.; Knabb, R. M.; Meade, R. P.; Quan, M. L.; Watson, C. A.; Wexler, R. R.; Wright, M. R.; Slee, A. M. Nonpeptide factor Xa inhibitors II. Antithrombotic evaluation in a rabbit model of electrically induced carotid artery thrombosis J. Pharmacol. Exp. Ther. 2000, 295, 212-218
38. Wong, P. C.; Crain, E. J.; Watson, C. A.; Zaspel, A. M.; Wright, M. R.; Lam, P. Y.; Pinto, D. J. P.; Wexler, R. R.; Knabb, R. M. Nonpeptide factor Xa inhibitors III. Effects of DPC423, an orally-active pyrazole antithrombotic agent, on arterial thrombosis in rabbits J. Pharmacol. Exp. Ther. 2000, 303, 993-1000
39. Himber, J.; Kirchhofer, D.; Riederer, M.; Tschopp, T. B.; Steiner, B.; Roux, S. P. Dissociation of antithrombotic effect and bleeding time prolongation in rabbits by inhibiting tissue factor function Thromb. Haemostasis 1997, 78, 1142-1149
40. Bird, J. E.; Smith, P. L.; Wang, X.; Schumacher, W. A.; Barbera, F.; Revelli, J.-P.; Seiffert, D. Effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice: murine ortholog of the Fletcher trait Thromb. Haemostasis 2012, 107, 1141-1150
41. Contour-Galcera, M.-O.; Poitout, L.; Moinet, C.; Morgan, B.; Gordon, T.; Roubert, P.; Thurieau, C. Synthesis of substituted imidazopyrazines as ligands for the human somatostatin receptor subtype 5 Bioorg. Med. Chem. Lett. 2001, 11, 741-745
42. Otwinowski, Z.; Minor, W. Macromolecular Crystallography. Part A; Carter, C. W., Sweet, R. M., Eds.; Methods in Enzymology, Vol. 276; Academic Press, Inc., San Diego, CA, 1997; pp 307-326.
43. 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
44. Emsley, P.; Lokhamp, B.; Scott, W. G.; Cowtan, K. Features and Development of Coot Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 486-501
45. Laskowski, R. A.; MacArthur, M. W.; Moss, D. S.; Thornton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures J. Appl. Crystallogr. 1993, 26, 283-291