Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker

Journal of Medicinal Chemistry

Volumn 60, Issue 3, 2017, Pages 1060-1075

  Corte, James R ^a   Fang, Tianan ^a   Osuna, Honey ^a   Pinto, Donald J P ^a   Rossi, Karen A ^a   Myers, Joseph E ^a   Sheriff, Steven ^a   Lou, Zhen ^a   Zheng, Joanna J ^a   Harper, Timothy W ^a   Bozarth, Jeffrey M ^a   Wu, Yiming ^a   Luettgen, Joseph M ^a   Seiffert, Dietmar A ^a   Decicco, Carl P ^a   Wexler, Ruth R ^a   Quan, Mimi L ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDE; BENZENE DERIVATIVE; BLOOD CLOTTING FACTOR 11A INHIBITOR; CARBAMIC ACID; CARBENE; CARBONYL DERIVATIVE; CYSTEINE; ETHYLENE; IMIDAZOLE; LEUCINE; MACROCYCLIC COMPOUND; BLOOD CLOTTING FACTOR 11A; LIGAND; SERINE PROTEINASE INHIBITOR;

ANTICOAGULATION; ARTICLE; BLOOD CLOTTING; CONFORMATION; CRYSTAL STRUCTURE; CYCLIZATION; DRUG DESIGN; HYDROGEN BOND; IN VITRO STUDY; RING CLOSING METATHESIS; X RAY CRYSTALLOGRAPHY; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DEVELOPMENT;

AMIDES; DRUG DISCOVERY; FACTOR XIA; HYDROGEN BONDING; LIGANDS; MACROCYCLIC COMPOUNDS; MOLECULAR STRUCTURE; SERINE PROTEINASE INHIBITORS;

EID: 85012180671     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b01460     Document Type: Article

References (72)

1. GBD 2013 Mortality and Causes of Death Collaborators 2013 Mortality and Causes of Death Collaborators. Global, Regional, and National Age-Sex Specific All-Cause and Cause-Specific Mortality for 240 Causes of Death, 1990-2013: A Systematic Analysis for the Global Burden of Disease Study 2013 Lancet 2015, 385, 117-171 10.1016/S0140-6736(14)61682-2
2. Morais, J.; De Caterina, R. Stroke prevention in atrial fibrillation: a clinical perspective on trials of the novel oral anticoagulants Cardiovasc. Drugs Ther. 2016, 30, 201-214 10.1007/s10557-015-6632-3
3. Schaefer, J. K.; McBane, R. D.; Wysokinski, W. E. How to choose appropriate direct oral anticoagulant for patient with nonvalvular atrial fibrillation Ann. Hematol. 2016, 95, 437-449 10.1007/s00277-015-2566-x
4. Levy, J. H.; Spyropoulos, A. C.; Samama, C. M.; Douketis, J. Direct oral anticoagulants J. Am. Coll. Cardiol. Intv. 2014, 7, 1333-1351 10.1016/j.jcin.2014.06.014
5. Cohen, A. T.; Spiro, T. E.; Buller, H. R.; Haskell, L.; Hu, D.; Hull, R.; Mebazaa, A.; Merli, G.; Schellong, S.; Spyropoulos, A. C.; Tapson, V. MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients N. Engl. J. Med. 2013, 368, 513-523 10.1056/NEJMoa1111096
6. Goldhaber, S. Z.; Leizorovicz, A.; Kakkar, A. K.; Haas, S. K.; Merli, G.; Knab, br M.; Weitz, J. I. ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients N. Engl. J. Med. 2011, 365, 2167-2177 10.1056/NEJMoa1110899
7. Mega, J. L.; Braunwald, E.; Wiviott, S. D.; Bassand, J.-P.; Bhatt, D. L.; Bode, C.; Burton, P.; Cohen, M.; Cook-Bruns, N.; Fox, K. A. A.; Goto, S.; Murphy, S. A.; Plotnikov, A. N.; Schneider, D.; Sun, X.; Verheugt, F. W. A.; Gibson, C. M. ATLAS ACS 2-TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome N. Engl. J. Med. 2012, 366, 9-19 10.1056/NEJMoa1112277
8. Alexander, J. H.; Lopes, R. D.; James, S.; Kilaru, R.; He, Y.; Mohan, P.; Bhatt, D. L.; Goodman, S.; Verheugt, F. W.; Flather, M.; Huber, K.; Liaw, D.; Husted, S. E.; Lopez-Sendon, J.; De Caterina, R.; Jansky, P.; Darius, H.; Vinereanu, D.; Cornel, J. H.; Cools, F.; Atar, D.; Leiva-Pons, J. L.; Keltai, M.; Ogawa, H.; Pais, P.; Parkhomenko, A.; Ruzyllo, W.; Diaz, R.; White, H.; Ruda, M.; Geraldes, M.; Lawrence, J.; Harrington, R. A.; Wallentin, L.; APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome N. Engl. J. Med. 2011, 365, 699-708 10.1056/NEJMoa1105819
9. Behnes, M.; Fastner, C.; Ansari, U.; Akin, I. New oral anticoagulants in coronary artery disease Cardiovasc. Hematol. Disord.: Drug Targets 2015, 15, 101-105 10.2174/1871529X1502151209111429
10. Oldgren, J.; Wallentin, L.; Alexander, J. H.; James, S.; Jonelid, B.; Steg, G.; Sundstrom, J. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis Eur. Heart J. 2013, 34, 1670-1680 10.1093/eurheartj/eht049
11. Emsley, J.; McEwan, P. A.; Gailani, D. Structure and function of factor XI Blood 2010, 115 ( 13 ) 2569-2577 10.1182/blood-2009-09-199182
12. Gailani, D.; Renne, T. Intrinsic pathway of coagulation and arterial thrombosis Arterioscler., Thromb., Vasc. Biol. 2007, 27 ( 12 ) 2507-2513 10.1161/ATVBAHA.107.155952
13. von dem Borne, P. A.; Meijers, J. C. M.; Bouma, B. N. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis Blood 1995, 86 ( 8 ) 3035-3042
14. Bane, C. E.; Neff, A. T.; Gailani, D. Factor XI deficiency or hemophilia C. In Hemostasis and Thrombosis: Practical Guidelines in Clinical Management; Saba, H. I.; Roberts, H. R., Eds.; John Wiley & Sons, Ltd.: Oxford, 2014; pp 71-81.
15. 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 ( 8 ) 4113-4117 10.1182/blood-2007-10-120139
16. Salomon, O.; Steinberg, D. M.; Dardik, R.; Rosenberg, N.; Zivelin, A.; Tamarin, I.; Ravid, B.; Berliner, S.; Seligsohn, U. Inherited factor XI deficiency confers no protection against acute myocardial infarction J. Thromb. Haemostasis 2003, 1, 658-661 10.1046/j.1538-7836.2003.00195.x
17. Salomon, O.; Steinberg, D. M.; Zucker, M.; Varon, D.; Zivelin, A.; Seligsohn, U. Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis Thromb. Haemostasis 2011, 105, 269-273 10.1160/TH10-05-0307
18. Doggen, C. J. M; Rosendaal, F. R.; Meijers, J. C. M. Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: opposite and synergistic effects of factor XI and XII Blood 2006, 108 ( 13 ) 4045-4051 10.1182/blood-2005-12-023697
19. Meijers, J. C. M.; Tekelenburg, W. L. H.; Bouma, B. N.; Bertina, R. M.; Rosendaal, F. R. High levels of coagulation factor XI as a risk factor for venous thrombosis N. Engl. J. Med. 2000, 342 ( 10 ) 696-701 10.1056/NEJM200003093421004
20. Bane, C. E.; Gailani, D. Factor XI as a target for antithrombotic therapy Drug Discovery Today 2014, 19 ( 9 ) 1454-1458 10.1016/j.drudis.2014.05.018
21. Muller, F.; Gailani, D.; Renne, T. Factor XI and XII as antithrombotic targets Curr. Opin. Hematol. 2011, 18, 349-355 10.1097/MOH.0b013e3283497e61
22. Yamashita, A.; Nishihira, K.; Kitazawa, T.; Yoshihashi, K.; Soeda, T.; Esaki, K.; Imamura, T.; Hattori, K.; Asada, Y. Factor XI contributes to thrombus propagation on injured neotima of the rabbit iliac artery J. Thromb. Haemostasis 2006, 4, 1496-1501 10.1111/j.1538-7836.2006.01973.x
23. Tucker, E. I.; Marzec, U. M.; White, T. C.; Hurst, S.; Rugonyi, S.; McCarty, O. J. T.; Gailani, D.; Gruber, A.; Hanson, S. R. Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI Blood 2009, 113 ( 4 ) 936-944 10.1182/blood-2008-06-163675
24. Gruber, A.; Hanson, S. R. Factor XI-dependence of surface-and tissue-initiated thrombus propagation in primates Blood 2003, 102 ( 3 ) 953-955 10.1182/blood-2003-01-0324
25. Crosby, J. R.; Marzec, U.; Revenko, A. S.; Zhao, C.; Gao, D.; Matafonov, A.; Gailani, D.; MacLeod, A. R.; Tucker, E. I.; Gruber, A.; Hanson, S.; Monia, B. P. Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates Arterioscler., Thromb., Vasc. Biol. 2013, 33, 1670-1678 10.1161/ATVBAHA.113.301282
26. Zhang, H.; Lowenberg, E. C.; Crosby, J. R.; MacLeod, A. R.; Zhao, C.; Gao, D.; Black, C.; Revenko, A. S.; Meijers, J. C. M.; Stroes, E. S.; Levi, M.; Monia, B. P. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk Blood 2010, 116, 4684-4692 10.1182/blood-2010-04-277798
27. Buller, H. R.; Bethune, C.; Bhanot, S.; Gailani, D.; Monia, B. P.; Raskob, G. E.; Segers, A.; Verhamme, P.; Weitz, J. I. Factor XI antisense oligonucleotide for prevention of venous thrombosis N. Engl. J. Med. 2015, 372, 232-240 The FXIa ASO work published subsequent to the work described herein. 10.1056/NEJMoa1405760
28. Schumacher, W. A.; Seiler, S. E.; Steinbacher, T. E.; Stewart, A. B.; Bostwick, J. S.; Hartl, K. S.; Liu, E. C.; Ogletree, M. L. Antithrombotic and hemostatic effects of small molecule factor XIa inhibitor in rats Eur. J. Pharmacol. 2007, 570, 167-174 10.1016/j.ejphar.2007.05.043
29. 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 10.1007/s11239-011-0599-0
30. Deng, H.; Bannister, T. D.; Jin, L.; Babine, R. E.; Quinn, J.; Nagafuji, P.; Celatka, C. A.; Lin, J.; Lazarova, T. I.; Rynkiewicz, M. J.; Bibbins, F.; Pandey, P.; Gorga, 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 10.1016/j.bmcl.2006.02.052
31. 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 peptidomimetic inhibitors of factor XIa as novel anticoagulants J. Med. Chem. 2006, 49, 7781-7791 10.1021/jm060978s
32. 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 of aryl boronic acids as potential inhibitors of factor XIa Bioorg. Med. Chem. Lett. 2006, 16, 5022-5027 10.1016/j.bmcl.2006.07.043
33. 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 10.1021/jm800314b
34. 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 ( 11 ) 4805-4818 10.1021/jm500311e
35. Sinha, D.; Badellino, K. O.; Marcinkiewicz, M.; Walsh, P. N. Allosteric modification of factor XIa functional activity upon binding to polyanions Biochemistry 2004, 43, 7593-7600 10.1021/bi049808c
36. 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. Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors J. Med. Chem. 2014, 57 ( 3 ) 955-969 10.1021/jm401670x
37. Wong, P. C.; Quan, M. L.; Watson, C. A.; Crain, E. J.; Harpel, M. R.; Rendina, A. R.; Luettgen, J. M.; Wexler, R. R.; Schumacher, W. A.; Seiffert, D. A. In vitro, antithrombotic and bleeding time studies of BMS-654457, a small-molecule, reversible and direct inhibitor of factor XIa J. Thromb. Thrombolysis 2015, 40 ( 4 ) 416-423 10.1007/s11239-015-1258-7
38. 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. Biarylmethyl indoline and indole analogs as potent and selective inhibitors of factor XIa. Presented at the 245th National Meeting of the American Chemical Society; American Chemical Society: New Orleans, LA, 2013; MEDI-415.
39. Hangeland, J. J.; Friends, T. J.; Rossi, K. A.; Smallheer, J. M.; Wang, C.; Sun, Z.; Corte, J. R.; Fang, T.; Wong, P. C.; Rendina, A. R.; Barbera, F. A.; Bozarth, J. M.; Luettgen, J. M.; Watson, C. A.; Zhang, G.; Wei, A.; Ramamurthy, V.; Morin, P. E.; Bisacchi, G. S.; Subramaniam, S.; Arunachalam, P.; Mathur, A.; Seiffert, D. A.; Wexler, R. R.; Quan, M. L. Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity J. Med. Chem. 2014, 57, 9915-9932 10.1021/jm5010607
40. Pinto, D. J. P; Smallheer, J. M.; Corte, J. R.; Austin, E. J. D.; Wang, C.; Fang, T.; Smith, L. M.; Rossi, K. A.; Rendina, A. R.; Bozarth, J. M.; Zhang, G.; Wei, A.; Ramamurthy, V.; Sheriff, S.; Myers, J. E.; Morin, P. E.; Luettgen, J. M.; Seiffert, D. A.; Quan, M. L.; Wexler, R. R. Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties Bioorg. Med. Chem. Lett. 2015, 25, 1635-1642 10.1016/j.bmcl.2015.01.028
41. Hu, Z.; Wong, P. C.; Gilligan, P. J.; Han, W.; Pabbisetty, K. B.; Bozarth, J. M.; Crain, E. J.; Harper, T.; Luettgen, J. M.; Myers, J. E.; Ramamurthy, V.; Rossi, K. A.; Sheriff, S.; Watson, C. A.; Wei, A.; Zheng, J. J.; Seiffert, D. A.; Wexler, R. R.; Quan, M. L. Discovery of a potent parenterally administered factor XIa inhibitor with hydroxyquinolin-2(1H)-one as the P2′ moiety ACS Med. Chem. Lett. 2015, 6, 590-595 10.1021/acsmedchemlett.5b00066
42. Corte, J. R.; Fang, T.; Hangeland, J. J.; Friends, T. J.; Rendina, A. R.; Luettgen, J. M.; Bozarth, J. M.; Barbera, F. A.; Rossi, K. A.; Wei, A.; Ramamurthy, V.; Morin, P. E.; Seiffert, D. A.; Wexler, R. R.; Quan, M. L. Pyridine and pyridinone-based factor XIa inhibitors Bioorg. Med. Chem. Lett. 2015, 25, 925-930 10.1016/j.bmcl.2014.12.050
43. Corte, J. R.; Fang, T.; Pinto, D. J. P.; Orwat, M. J.; Rendina, A. R.; Luettgen, J. M.; Rossi, K. A.; Wei, A.; Ramamurthy, V.; Myers, J. E.; Sheriff, S.; Narayanan, R.; Harper, T. W.; Zheng, J. J.; Li, Y.; Seiffert, D. A.; Wexler, R. R.; Quan, M. L. Orally bioavailable pyridine and pyrimidine-based factor XIa inhibitors: discovery of the methyl N-phenyl carbamate P2 prime group Bioorg. Med. Chem. 2016, 24, 2257-2272 10.1016/j.bmc.2016.03.062
44. Smith, L. M.; Orwat, M. J.; Hu, Z.; Han, W.; Wang, C.; Rossi, K. A.; Gilligan, P. J.; Pabbisetty, K. B.; Osuna, H.; Corte, J. R.; Rendina, A. R.; Luettgen, J. M.; Wong, P. C.; Narayanan, R.; Harper, T. W.; Bozarth, J. M.; Crain, E. J.; Wei, A.; Ramamurthy, V.; Morin, P. E.; Xin, B.; Zheng, J.; Seiffert, D. A.; Quan, M. L.; Lam, P. Y. S.; Wexler, R. R.; Pinto, D. J. P. Novel phenylalanine derived diamides as factor XIa inhibitors Bioorg. Med. Chem. Lett. 2016, 26, 472-478 10.1016/j.bmcl.2015.11.089
45. An active site reversible FXIa inhibitor based on a diamide chemotype was also recently disclosed, please see: Fjellstrom, O.; Akkaya, S.; Beisel, H. G.; Eriksson, P. O.; Erixon, K.; Gustafsson, D.; Jurva, U.; Kang, D.; Karis, D.; Knecht, W.; Nerme, V.; Nilsson, I.; Olsson, T.; Redzic, A.; Roth, R.; Sandmark, J.; Tigerstrom, A.; Oster, L. Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design PLoS One 2015, 10, e0113705 10.1371/journal.pone.0113705
46. Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. The exploration of macrocycles for drug discovery-an underexploited structural class Nat. Rev. Drug Discovery 2008, 7 ( 7 ) 608-624 10.1038/nrd2590
47. Marsault, E.; Peterson, M. L. Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery J. Med. Chem. 2011, 54, 1961-2004 10.1021/jm1012374
48. Mallinson, J.; Collins, I. Macrocycles in new drug discovery Future Med. Chem. 2012, 4, 1409-1438 10.4155/fmc.12.93
49. Giordanetto, F.; Kihlberg, J. Macrocyclic drugs and clinical candidates: what can medicinal chemists learn from their properties? J. Med. Chem. 2014, 57, 278-295 10.1021/jm400887j
50. Nantermet, P. G.; Barrow, J. C.; Newton, C. L.; Pellicore, J. M.; Young, M.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; McMasters, D. R.; Yan, Y.; Kuo, L. C.; Vacca, J. P.; Selnick, H. G. Design and synthesis of potent and selective macrocyclic thrombin inhibitors Bioorg. Med. Chem. Lett. 2003, 13, 2781-2784 10.1016/S0960-894X(03)00506-7
51. For studies on the macrocyclic natural product cyclotheonamide A, please see: Greco, M. N.; Powell, E. T.; Hecker, L. R.; Andrade-Gordon, P.; Kauffman, J. A.; Lewis, J. M.; Ganesh, V.; Tulinsky, A.; Maryanoff, B. E. Novel thrombin inhibitors that are based on a macrocyclic tripeptide motif Bioorg. Med. Chem. Lett. 1996, 6, 2947-2952 10.1016/S0960-894X(96)00554-9
52. Priestley, E. S.; Cheney, D. L.; DeLucca, I.; Wei, A.; Luettgen, J. M.; Rendina, A. R.; Wong, P. C.; Wexler, R. R. Structure-based design of macrocyclic coagulation factor VIIa inhibitors J. Med. Chem. 2015, 58, 6225-6236 10.1021/acs.jmedchem.5b00788
53. Van Lierop, B. J.; Lummiss, J. A. M.; Fogg, D. E. Ring-closing metathesis. In Olefin Metathesis: Theory and Practice; Grela, K., Ed.; John Wiley & Sons Inc.: Hoboken, NJ, 2014; pp 85-152.
54. Contour-Galcera, M.; 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 10.1016/S0960-894X(01)00051-8
55. Zou, G.; Reddy, Y. K.; Falck, J. R. Ag(I)-promoted Suzuki-Miyaura cross-coupling of n-alkylboronic acids Tetrahedron Lett. 2001, 42, 7213-7215 10.1016/S0040-4039(01)01536-2
56. Kim, J.; Chang, S. Ammonium salts as an inexpensive and convenient nitrogen source in the Cu-catalyzed amination of aryl halides at room temperature Chem. Commun. 2008, 3052-3054 10.1039/b804637a
57. Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Preparation of N-aryl compounds by amino acid-promoted Ullmann-type coupling reactions Synthesis 2005, 496-499 It was interesting to note that the azide was reduced to the aniline in situ which had not been observed in this reference 10.1055/s-2004-831196
58. Chen, Y.; Dias, H. V. R.; Lovely, C. J. Synthesis of fused bicyclic imidazoles by ring-closing metathesis Tetrahedron Lett. 2003, 44, 1379-1382 10.1016/S0040-4039(02)02864-2
59. The Z-alkene analogues in both the 12-and 13-membered alkyl-linked macrocycles showed a significant loss in FXIa activity; unpublished results from Corte, J.
60. The increase in dihedral angle was a common feature for the macrocyclic series. The X-ray crystal structure of the 12-membered macrocycle 3 revealed a 23° increase in the dihedral angle of the P2 prime phenyl compared to acyclic phenyl imidazole 1; unpublished results from Sheriff, S. and Rossi, K. A.
61. The NH of the carbamate forms a hydrogen bond with the carbonyl of His40 (2.9 Å) and the carbonyl of the carbamate forms a hydrogen bond through a conserved water to Ile151 (2.7 Å).
62. For numbering, the benzylic carbon of the macrocyclic linker is designated C1. The distances from the linker in macrocycle 9 to the disulfide bridge are: C3 to CYS42 (5.6Å) and CYS58 (6.5Å), C4 to CYS42 (4.4Å) and CYS58 (5.1Å), and C5 to CYS42 (4.2Å) and CYS58 (4.7Å).
63. The significant loss in FXIa affinity, on going from the amide/carbamate-linked macrocycles to the amine-linked macrocycle, may not be entirely due to the difference in H-bond donor ability of these different groups. We speculate that the amide/carbamate moieties also serve to reduce the conformational entropy of the macrocycle ring by rigidifying the macrocyclic linker.
64. The distances from the linker in macrocycle 16 to the disulfide bridge are: αC to CYS42 (4.4Å) and CYS58 (5.6Å), βC to CYS42 (4.8Å) and CYS58 (5.5Å), and γC to CYS42 (4.7Å) and CYS58 (5.3Å). The distances from the linker in macrocycle 13 to the disulfide bridge are: αC to CYS42 (4.6Å) and CYS58 (5.6Å), βC to CYS42 (4.8Å) and CYS58 (5.5Å), and γC to CYS42 (4.4Å) and CYS58 (5.0Å).
65. 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.; Knab, br M.; He, K.; Xin, B.; Wexler, R. R.; Lam, P. Y. S. Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl] phenyl)-4, 5, 6, 7-tetrahydro-1H-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 ( 22 ) 5339-5356 10.1021/jm070245n
66. The amino acid sequence of plasma kallikrein has 58% homology to FXI, please see: Renne, T.; Gailani, D.; Meijers, J. C. M.; Muller-Esterl, W. Characterization of the H-kininogen-binding site on factor XI: a comparison of factor XI and plasma prekallikrein J. Biol. Chem. 2002, 277, 4892-4899 10.1074/jbc.M105221200
67. Otwinowski, Z.; Minor, W. Processing of X-ray Diffraction Data Collected in Oscillation Mode. Methods in Enzymology: Macromolecular Crystallography. Part A; Vol. 276; Carter, C. W.; Sweet, R. M., Eds.; Academic Press, Inc.: San Diego, CA, 1997; pp 307-326.
68. Navaza, J. AMoRe: an automated package for molecular replacement Acta Crystallogr., Sect. A: Found. Crystallogr. 1994, 50, 157-163 10.1107/S0108767393007597
69. Navaza, J.; Vernoslova, E. On the fast translation functions for molecular replacement Acta Crystallogr., Sect. A: Found. Crystallogr. 1995, 51, 445-449 10.1107/S0108767394011335
70. Collaborative Computational Project, Number 4 The CCP4 suite: programs for protein crystallography Acta Crystallogr., Sect. D: Biol. Crystallogr. 1994, 50, 760-763 10.1107/S0907444994003112
71. 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 10.1107/S0907444904016427
72. Emsley, P.; Lohkamp, B.; Scott, W. G.; Cowtan, K. Features and development of Coot Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 486-501 10.1107/S0907444910007493