Non-amidine-containing 1,2-dibenzamidobenzene inhibitors of human factor Xa with potent anticoagulant and antithrombotic activity [2]

Journal of Medicinal Chemistry

Volumn 43, Issue 11, 2000, Pages 2087-2092

  Masters, John J ^a   Franciskovich, Jeffry B ^a   Tinsley, Jennifer M ^a   Campbell, Charles ^a   Campbell, Jack B ^a   Craft, Trelia J ^a   Froelich, Larry L ^a   Gifford Moore, Donetta S ^a   Hay, Lynne A ^a   Herron, David K ^a   Klimkowski, Valentine J ^a   Kurz, Kenneth D ^a   Metz, James T ^a   Ratz, Andrew M ^a   Shuman, Robert T ^a   Smith, Gerald F ^a   Smith, Tommy ^a   Towner, Richard D ^a   Wiley, Michael R ^a   Wilson, Alex ^a   Yee, Ying K ^a   more..

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,2 DIBENZAMIDOBENZENE DERIVATIVES; ANTICOAGULANT AGENT; BENZENE DERIVATIVE; BLOOD CLOTTING FACTOR 10A INHIBITOR; UNCLASSIFIED DRUG;

ANTICOAGULATION; DRUG POTENCY; FIBRINOLYTIC THERAPY; HUMAN; LETTER; THROMBOSIS;

ANIMALS; ANTICOAGULANTS; BENZAMIDES; BENZENE DERIVATIVES; DISEASE MODELS, ANIMAL; FACTOR XA; FIBRINOLYTIC AGENTS; HUMANS; PIPERIDINES; RABBITS; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBOSIS;

EID: 0034213954     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990625b     Document Type: Letter

References (47)

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16. Among the first, and most potent, small molecule inhibitors of fXa were the diamidine-or guanidine-containing constructs. (a) Nagahara, T.; Yokoyama, Y.; Inamura, K.; Katakura, S.; Komoriya, S.; Yamaguchi, H.; Hara, T.; Iwamoto, M. Dibasic (Amidinoaryl)propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors. J. Med. Chem. 1994, 37, 1200-1207.
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18. (c) Taniuchi, Y.; Sakai, Y.; Hisamichi, N.; Kayama, M.; Mano, Y.; Sato, K.; Hirayama, F.; Koshio, H.; matsumoto, Y.; Kawasaki, T. Biochemical and Pharmacological Characterization of YM-60828, a newly Synthesized and Orally Active Inhibitor of Human Factor Xa. Thromb. Haemostasis. 1998, 79 (3), 543-548.
19. (d) Shaw, K. J.; Guilford, W. J.; Dallas, J. L.; Koovakaat, S. K.; Liang, A.; Light, D. R.; Morrissey, M. M. (Z,Z)-2,7-Bis(4-amidinobenzylidene)cycloheptan-1-one: Identification of a Highly Active Inhibitor of Blood Coagulation Factor Xa. J. Med. Chem. 1998, 41, 3551-3556.
20. (e) Phillips, G. B.; Buckmann, B. O.; Davey, D. D.; Eagen, K. A.; Guilford, W. J.; Hinchman, J.; Ho, E.; Koovakkat, S.; Liang, A.; Light, D. R.; Mohan, R.; Ng, H. P.; Post, J. M.; Shaw, K. J.; Smith, D.; Subramanyam, B.; Sullivan, M. E.; Trinh, L.; Vergona, R.; Walters, J.; White, K.; Whitlow, M.; Wu, S.; Xu, W.; Morrissey, M. M. Discovery of N-[2-[5-[Amino(imino)methyl]-2-hydroxyphenoxy]-3,5-difluor-6-[3-(4,5-dihydro-1- methyl-1H-imidazol-2-yl)-phenoxy]pyridin-4-yl]-N-methylglycine (ZK-807834): A Potent, Selective, and Orally Active Inhibitor of the Blood Coagulation Enzyme Factor Xa. J. Med. Chem. 1998, 41, 3557-3562.
21. (f) Gabriel, B.; Stubbs, M. T.; Bergner, A.; Hauptmann, J.; Bode, W.; Sturzebecher, J.; Moroder, L. Design of Benzamidine-Type Inhibitors of Factor Xa. J. Med. Chem. 1998, 41, 4240.
22. (g) Maduskuie, T. P.; McNamara, K. J.; Ru, Y.; Knabb, R. M.; Stouten, P. F. W. Rational Design and Synthesis of Novel, Potent Bis-phenylamidine Carboxylate Factor Xa Inhibitors. J. Med. Chem. 1998, 41, 53-62.
23. (h) Quan, M. L.; Pruitt, J. R.; Ellis, C. D.; Liauw, A. Y.; Galemmo, R. A., Jr.; Stouten, P. F. W.; Wityak, J.; Knabb, R. M.; Thoolen, M. J.; Wong, P. C.; Wexler, R. R. Bisbenzamidine Isoxazoline Derivative as Factor Xa Inhibitors. Bioorg. Med. Chem. Lett. 1997, 7 (21), 2813-2818.
24. (i) von der Saal, W.; Engh, R. A.; Eichinger, A.; Gabriel, B.; Kucznierz, R.; Sauer, J. Synthesis and Selective Inhibitory Activities of Terphenyl-Bisamidines for Serine Proteases. Arch. Pharm. Pharm. Med. Chem. 1996, 329, 73-82.
25. There are limited reports of nonamidine inhibitors of fXa. (a) Novel Aminoheterocyclic Derivatives as Inhibitors of Factor Xa. Expert Opin. Ther. Pat. 1996, 6 (8), 795-799.
26. (b) Choi-Sledeski, Y. M.; Becker, M. R.; Green, D. M.; Davis, R.; Ewing, W. R.; Mason, H. J.; Ly, C.; Spada, A.; Liang, G.; Cheney, D.; Barton, J.; Chu, V.; Brown, K.; Colussi, D.; Bentley, R.; Leadley, R. J.; Dunwiddie, C.; Pauls, H. W. Aminoisoquinolines: Design and Synthesis of an Orally Active Benzamidine Isostere for the Inhibition of Factor Xa. Bioorg. Med. Chem. Lett. 1999, 9 (17), 2539-2544.
27. (c) Choi-Sledeski, Y. M.; Pauls, H. W.; Ewing, W. R.; Spada, A. P.; Green, D. M.; Davis, R.; Ly, C.; Gardiner, C. J.; Gong, Y.; Jiang, J.; Li, A.; Mason, H. J.; Liang, G.; Chu, V.; Brown, K.; Colussi, D.; Morgan, S. R.; Leadley, R. J. Design, Structure Activity Relationships and Initial Biological Activity of Novel Non-Benzamidine Inhibitors of Factor Xa. Presented at the 217th National Meeting of the American Chemical Society, Anaheim, CA, March 21-25 1999, Abstract MEDI-80.
28. This binding orientation of the 1,2-dibenzamidobenzenes was proposed from molecular modeling studies and SAR, and it was indirectly confirmed by X-ray crystallography of a related analogue complexed with the highly homologous a-thrombin. See refs 4 and 8.
29. Wiley, M. R.; Weir, L. C.; Briggs, S.; Bryan, N. A.; Buben, J.; Campbell, C.; Chirgadze, N. Y.; Conrad, R. C.; Craft, T. J.; Francoiskovich, J. B.; Froelich, L. L.; Gifford-Moore, D. S.; Goodson, T., Jr.; Herron, D. K.; Klimkowski, V. J.; Kurz, K. D.; Kyle, J. A.; Masters, J. J.; Ratz, A. M.; Milot, G., Shuman, R. T.; Smith, T.; Smith, G. F.; Tebbe, A. L.; Tinsley, J. M.; Towner, R. D.; Wilson, A.; Yee, Y. K. The Structure-Based Design of Potent, Amidine-Derived Inhibiotrs of Factor Xa: Evaluation of Selectivity, Anticoagulant Activity and Antithrombotic Activity. J. Med. Chem. 2000, 43 (5), 883-899.
30. ass), and prothrombin time (PT) measurements were conducted as previously described in ref 7 and the following: Smith, G. F.; Shuman, R. T.; Craft, T. J.; Gifford-Moore, D. S.; Kurz, K. D.; Jones, N. D.; Chirgadze, N.; Hermann, R. B.; Coffman, W. J.; Sandusky, G. E.; Roberts, E.; Jackson, C. V. A Family of Arginal Inhibitors Related to Efegatran. Semin. Thromb. Hemostasis 1996, 22 (2), 173-183.
31. Efforts to enhance the pharmacokinetic properties of early diamidine fXa inhibitor leads have focused on removing amidine functionality. (a) Fevig, J. M.; Buriak, J., Jr.; Stouten, P. F. W.; Knabb, R. M.; Lam, G. N.; Wong, P. C.; Wexler, R. R. Preparation of Pyrrolidine and Isoxazolidine Benzamidines as Potent Inhibitors of Coagulation Factor Xa. Bioorg. Med. Chem. Lett. 1999, 9 (8), 1195-1200.
32. (b) Fevig, J. M.; Cacciola, J.; Alexander, R. S.; Knabb, R. M.; Lam, G. N.; Wong, P. C.; Wexler, R. R. Preparation of meta-Amidino-N,N-Disubstituted Anilines as Potent Inhibitors of Coagualtion Factor Xa. Bioorg. Med. Chem. Lett. 1998, 8 (22), 3143-3148.
33. (c) Galemmo, R. A., Jr.; Maduskuie, T. P.; Dominguez, C.; Rossi, K. A.; Knabb, R. M.; Wexler, R. R.; Stouten, P. F. W. The De Novo Design and Synthesis of Cyclic Urea inhibitors of Factor Xa: Initial SAR studies. Bioorg. Med. Chem. Lett. 1998, 8 (19), 2705-2710.
34. (d) Buckman, B. O.; Mohan, R.; Koovakkat, S.; Liang, A.; Trinh, L.; Morrissey, M. M. Design, Synthesis, and Biological Activity of Novel Purine and Bicyclic Pyrimidine Factor Xa Inhibitors. Bioorg. Med. Chem. Lett. 1998, 8 (16), 2235-2240.
35. (e) Klein, S. I.; Czekaj, M.; Gardner, C. J.; Guertin, K. R.; Cheney, D. L.; Spada, A. P.; Bolton, S. A.; Brown, K.; Colussi, D.; Heran, C. L.; Morgan, S. R.; Leadley, R. J.; Dunwiddie, C. T.; Perrone, M. H.; Chu, V. Identification and Initial Structure-Activity Relationships of a Novel Class of Nonpeptide Inhibitors of Blood Coagulation Factor Xa. J. Med. Chem. 1998, 41, 437-450.
36. For an account of the detrimental effects on anticoagulant activity due to increased plasma protein binding and lipophilicity in a series of IIa inhibitors, see: Tucker, T. J.; Lumma, W. C.; Lewis, S. D.; Gardell, S. J.; Lucas, B. J.; Baskin, E. P.; Woltmann, R.; Lynch, J. J.; Lyle, E. A.; Appleby, S. D.; Chen, I.-W.; Dancheck, K. B.; Vacca, J. P. Potent Noncovalent Thrombin Inhibitors that Utilize the Unique Amino Acid D-Dicyclohexylalanine in the P3 Position. Implications on Oral Bioavailability and Antithrombotic Efficacy. J. Med. Chem. 1997, 40, (11), 1565-1569.
37. The 1-(4-pyridyl)piperidine group has been incorporated into other unique series of fXa inhibitors. (a) Kunitada, S.; Nagahara, T. Factor Xa Inhibitors. Curr. Pharm. Des. 1996, 2, 531-542.
38. (b) Faull, A. W.; Mayo, C. M.; Preston, J.; Stocker, A. Aminoheterocyclic Derivatives as Antithrombotic or Anticoagulant Agents. W09610022, 1996.
39. (c) Takayanagi, M.; Sagi, K.; Nakagawa, T.; Yamanashi, M.; Kayahara, T.; Takshan, S.; Fukuda, Y.; Takahashi, M.; Shoji, M. Benzamidine Derivatives WO-09831661, 1998.
40. 1H NMR, MS) and elemental analysis data consistent with their structure. See Supporting Information for details.
41. Ali, N. M.; McKillop, A.; Mitchell, M. B.; Rebelo, R. A.; Wallbank, P. J. Palladium-Catalysed Cross-Coupling Reactions of Arylboronic Acids with π-Deficient Heteroaryl Chlorides. Tetrahedron 1992, 48 (37), 8117-8126.
42. 4,7 The charges assigned to each ligand were smoothed to give a total sum of 1.0. The initial position of the water complexed to the ligaud in the S4′ region was taken from the X-ray crystallographic water 518 of the 1HCG fXa coordinate set. Key binding interactions of 4 with fXa include: (a) hydrophobic interactions of methoxyphenyl group with Si-site, (b) H-bonding of the 1,2-bisamide with Gly218, (c) the pyridine ring of 4 with the "aryl binding" site of S4 composed of residues Tyr99, Phe174, and Trp215, and
43. H-bonding with protonated pyridine of 4 and a buried water molecule in S4-S4′-site which is further hydrogen bonded to carbonyl oxygens of Thr98 and Ile175 and the hydroxyl of Thr98 in fXa. Although positioning of water within the context of a molecular force field is uncertain, a similar interaction was observed in the X-ray structure determination of des[1-44]fXa with the amidine-containing 4-aminopyridine fXa inhibitor FX-2212a: Kamata, K.; Kawamoto, H.; Honma, T.; Iwama, T.; Kim, S. H. Structural Basis for Chemical Inhibition of Human Blood Coagulation Factor Xa. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 6630-6635.
44. 3a a series of exposed carbonyl groups consisting of residues Glu97, Thr98, Ile175, and Thr176 of fXa (Figure 2).
45. a, values for compounds 2, 4, and 23 were 11.0 ± 0.2 (3.9 ± 0.1-acid), 8.7 ± 0.02, and 8.9 ± 0.1, respectively. The LogD values measured at pH = 7.4 for compounds 2, 4, and 23 were -1.0, 1.1, and 1.9, respectively.
46. 8 The dose response of prothrombin clotting times in various species plasma for 2 and 23 was determined as described in ref 8. The PT concentrations of 2 and 23 in rabbit plasma were 0.84 ± 0.05 μM and 0.78 ± 0.03 μM, respectively. The PT for 23 was > 20 μM in both rat and dog plasma.
47. For a discussion on the importance of enzyme binding selectivity, see: Wiley, M. R.; Chirgadze, N. Y.; Clawson, D. K.; Gifford-Moore, D. S.; Jones, N. D.; Olkowski, J. L.; Schacht, A. L.; Weir, L. C.; Smith, G. F. Serine Protease Selectivity of the Thrombin Inhibitor D-Phe-Pro-Agmatine and its Homologues. Bioorg. Med. Chem. Lett. 1995, 5 (23), 2835-2840 and references therein.