Efficacious and orally bioavailable thrombin inhibitors based on a 2,5-thienylamidine at the P1 position: Discovery of N-carboxymethyl-D-diphenylalanyl-L-prolyl[(5-amidino-2- thienyl)methyllamide

Journal of Medicinal Chemistry

Volumn 46, Issue 17, 2003, Pages 3612-3622

  Lee, Koo ^a   Park, Cheol Won ^a   Jung, Won Hyuk ^a   Park, Hee Dong ^a   Lee, Sun Hwa ^a   Chung, Kyung Ha ^a   Park, Su Kyung ^a   Kwon, O Hwan ^a   Kang, Myunggyun ^a   Park, Doo Hee ^a   Lee, Sang Koo ^a   Kim, Eunice E ^a   Yoon, Suk Kyoon ^a   Kim, Aeri ^a  

^a LG Chemical Ltd   (South Korea)

Author keywords

[No Author keywords available]

Indexed keywords

2,5 THIENYLAMIDINE; AMIDINE; ANTIVITAMIN K; ARGATROBAN; ENOXAPARIN; HEPARIN; LB 30057; LB 30812; LB 30870; LOW MOLECULAR WEIGHT HEPARIN; N AMINOSULFONYL DEXTRO DIPHENYLALANYLPROLYL[(4 AMIDINOPHENYL)METHYL]AMIDE; N AMINOSULFONYL DEXTRO DIPHENYLALANYLPROPYL[(4 AMIDINO 3 FLUOROPHENYL)METHYL]AMIDE; N CARBOXYMETHYL DEXTRO DIPHENYLALANYLPROLYL[(5 AMIDINO 2 THIENYL)METHYL]AMIDE; SULFAMIDE DERIVATIVE; SULFONAMIDE; THROMBIN; THROMBIN INHIBITOR; UNCLASSIFIED DRUG; WARFARIN;

AMINO TERMINAL SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTERY THROMBOSIS; ARTICLE; BLOOD CLOTTING; CONTROLLED STUDY; DERIVATIZATION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG STABILITY; GRAVIMETRY; HUMAN; HUMAN TISSUE; MALE; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; VEIN THROMBOSIS;

ADMINISTRATION, ORAL; AMIDINES; ANIMALS; ANTICOAGULANTS; BIOLOGICAL AVAILABILITY; CRYSTALLOGRAPHY, X-RAY; DIPEPTIDES; DOGS; DRUG STABILITY; FIBRINOLYTIC AGENTS; HAPLORHINI; HUMANS; LIVER; MALE; MODELS, MOLECULAR; PROTEASE INHIBITORS; RABBITS; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; SULFANILAMIDES; THROMBIN; VENOUS THROMBOSIS;

EID: 0041731604     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm030025j     Document Type: Article

References (44)

1. (a) Kimball, S. D. Challenges in the Development of Orally Bioavailable Thrombin Active Site Inhibitors. Blood Coagulation Fibrinolysis 1995, 6, 511-519.
2. (b) Shafer, J. A. Cardiovascular Chemotherapy: Anticoagulants. Curr. Opin. Chem. Biol. 1998, 2, 458-465.
3. (c) Adang, A. E. P.; Rewinkel, J. B. M. A New Generation of Orally Active Antithrombotics: Comparing Strategies in the GPIIb/IIIa, Thrombin and Factor Xa Areas. Drugs Future 2000, 25, 369-383.
4. (d) Weitz, J. I.; Crowther, M. Direct Thrombin Inhibitors. Thromb. Res. 2002, 106, V275-V284.
5. For recent reviews, see the following. (a) Hauptmann, J.; Sturzebecher, J. Synthetic Inhibitors of Thrombin and Factor Xa: From Bench to Bedside. Thromb. Res. 1999, 93, 203-241. (b) Sanderson, P. E. J. Small, Noncovalent Serine Protease Inhibitors. Med. Res. Rev. 1999, 19, 179-197. (c) Vacca, J. P. New Advances in the Discovery of Thrombin and Factor Xa Inhibitors. Curr. Opin. Chem. Biol. 2000, 25, 369-383.
6. For recent reviews, see the following. (a) Hauptmann, J.; Sturzebecher, J. Synthetic Inhibitors of Thrombin and Factor Xa: From Bench to Bedside. Thromb. Res. 1999, 93, 203-241. (b) Sanderson, P. E. J. Small, Noncovalent Serine Protease Inhibitors. Med. Res. Rev. 1999, 19, 179-197. (c) Vacca, J. P. New Advances in the Discovery of Thrombin and Factor Xa Inhibitors. Curr. Opin. Chem. Biol. 2000, 25, 369-383.
7. For recent reviews, see the following. (a) Hauptmann, J.; Sturzebecher, J. Synthetic Inhibitors of Thrombin and Factor Xa: From Bench to Bedside. Thromb. Res. 1999, 93, 203-241. (b) Sanderson, P. E. J. Small, Noncovalent Serine Protease Inhibitors. Med. Res. Rev. 1999, 19, 179-197. (c) Vacca, J. P. New Advances in the Discovery of Thrombin and Factor Xa Inhibitors. Curr. Opin. Chem. Biol. 2000, 25, 369-383.
8. (a) Oh, Y. S.; Yun, M.; Hwang, S. Y.; Hong, S.; Shin, Y.; Lee, K.; Yoon, K. H.; Yoo, Y. J.; Kim, D. S.; Lee, S. H.; Lee, Y. H.; Park, H. D.; Lee, C. H.; Lee, S. K.; Kim, S. Discovery of LB30057, a Benzamidrazone-Based Selective Oral Thrombin Inhibitor. Bioorg. Med. Chem. Lett. 1998, 8, 631-634.
9. (b) Kim, I.-C.; Oh, Y. S.; Yun, M.; Hwang, S. Y.; Hong, S.; Lee, Y. H.; Lee, K.; Kim, S.; Yoo, Y. J.; Yoon, K. H.; Kim, D. S.; Lee, C. H. Circulation 1997, 96, I-41.
10. (a) Chi, L.; Mertz, T. E.; Rogers, K. L.; Janiczek, N.; Peng, Y. W.; Saganek, L.; Bousley, R. F.; Juneau, P. L.; Uprichard, A. C.; Gallogher, K. P. Antithrombotic Effect of LB30057 (CI-1028), a New Synthetic Thrombin Inhibitor, in a Rabbit Model of Thrombosis: Comparison with Inogatran. J. Thromb. Thrombolysis 2001, 11, 19-31.
11. (b) McClanahan, T. B.; Hicks, G. W.; Ignasiak, D. P.; Bousley, R. F.; Mertz, T. E.; Juneau, P. L.; Janiczek-Dolpihin, N.; Kim, I. C.; Gallogher, K. P. The Antithrombotic Effect of CI-1028, an Orally Bioavailable Direct Thrombin Inhibitor, in a Canine Model of Venous and Arterial Thrombosis. J. Thromb Thrombolysis 2000, 10, 277-284.
12. Lee, K.; Jung, W.-H.; Park, C. W.; Hong, C. Y.; Kim, I. C.; Kim, S.; Oh, Y. S.; Kwon, O. H.; Lee, S.-H.; Park, H. D.; Kim, S. W.; Lee, Y. H.; Yoo, Y. J. Benzylamine-Based Selective and Orally Bioavailable Inhibitors of Thrombin. Bioorg. Med. Chem. Lett. 1998, 8, 2563-2568.
13. Wiley, M. R.; Chirgadze, N. Y.; Clawson, D. K.; Craft, T. J.; Gifford-Moore, D. S.; Jones, N. D.; Olkowski, J. L.; Schacht, A. L.; Weir, L. C.; Smith, G. F. D-Phe-Pro-p-Amidinobenzylamine: A Potent and Highly Selective Thrombin Inhibitor. Bioorg. Med. Chem. 1995, 5, 2835-2391.
14. Stone, S. R.; Tapparelli, C. Thrombin Inhibitors as Antithrombotic Agents: The Importance of Rapid Inhibition. J. Enzyme Inhib. 1995, 9, 3-15.
15. Elg, M.; Gustafson, D.; Deinum, J. The Importance of Enzyme Inhibition Kinetics for the Effect of Thrombin Inhibitors in a Rat Model of Arterial Thrombosis. Thromb. Haemostasis 1997, 78, 1286-1292.
16. Lee, K.; Jung, W.-H.; Kang, M.; Lee, S.-H. Noncovalent Thrombin Inhibitors Incorporating an Imidazolylethynyl P1. Bioorg. Med. Chem. Lett. 2000, 10, 2775-2278.
17. (a) Tucker, T. J.; Lumma, W. C.; Mulichak, A. M.; Chen, Z.; Naylor-Olsen, A. M.; Lewis, S. D.; Lucas, R.; Freidinger, R. M.; Kuo, L. C. Design of Highly Potent Noncovalent Inhibitors That Utilize a Novel Lipophilic Binding Pocket in the Thrombin Active Site. J. Med. Chem. 1997, 40, 830-832.
18. (b) Feng, D.-M.; Gardell, S. J.; Lewis, S. D.; Bock, M. G.; Chen, Z.; Freidinger, R. M.; Naylor-Olsen, A. M.; Ramjit, H. G.; Woltmann, R.; Baskin, E. P.; Lynch, J. J.; Lucas, R.; Shafer, J. A.; Chen, I.-W.; Dancheck, K. B.; Mao, S.-S.; Krueger, J. A.; Hare, T. R.; Mulichak, A. M.; Vacca, J. P. Discovery of a Novel Selective and Orally Bioavailable Class of Thrombin Inhibitors. J. Med. Chem. 1997, 40, 3726-3733.
19. (c) Cheng, L.; Goodwin, C. A.; Schully, M. F.; Kakkar, V. V.; Claeson, G. J. Med. Chem. 1992, 35, 3364.
20. Pinto, D. J. P.; Orwat, M. J.; Wang, S.; Fevig, J. M.; Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.; Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.; Liang, L.; Aungst, B. J.; Wright, M. R.; Knabb, R. M.; Wong, P. C.; Wexler, R. R.; Lam, P. Y. S. Discovery of 1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1, 1′-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa. J. Med. Chem. 2001, 44, 566-578.
21. Ho, J. Z.; Gibson, T. S.; Semple, J. E. Novel, Potent Non-Covalent Thrombin Inhibitors Incorporating P3-Lactam Scaffolds. Bioorg. Med. Chem. 2002, 12, 743-748.
22. Lee, K.; Jung, W.-H.; Hwang, S. Y.; Lee, S.-H. Noncovalent Tripeptidic Thrombin Inhibitors Incorporating Amidrazone, Amine and Amidine Functions at P1. Bioorg. Med. Chem. Lett. 2002, 12, 1017-1022.
23. Lee, K.; Jung, W.-H.; Park, C. W.; Park, H. D.; Lee, S. H.; Kwon, O. W. Fluorobenzamidrazone Thrombin Inhibitors: Influence of Fluorine on Enhancing Oral Absorption. Bioorg. Med. Chem. Lett. 1999, 9, 2483-2486.
24. The use of 2,5-thienylamidine P1 as a benzamidine surrogate for thrombin inhibitors was described in our previous communications; see ref 11 and the following. Lee, K.; Hwang, S. Y.; Yun, M.; Kim, D. S. Potent and Efficacious Thienylamindine-Incorporated Thrombin Inhibitors. Bioorg. Med. Chem. 1998, 6, 1683-1686. This P1 element was also utilized by other research groups; see the following. Reiner, J. E.; Sieve, D. V.; Araldi, G.-L.; Cui, J. J.; Ho, J. Z.; Reddy, K. M.; Mamedova, L.; Vu, P. H.; Lee, K.-S. S.; Minami, N. K.; Gibson, T. S.; Anderson, S. M.; Brabury, A. E.; Nolan, T. G.; Semple, J. E. Non-Covalent Thrombin Inhibitors Featuring P3-Heterocycles with P1-Monocyclic Arginine Surrogates. Bioorg. Med. Chem. 2002, 12, 1203-1208. Lange, U. E. W.; Zechel, C. Solid-Phase Synthesis of Thrombin Inhibitors. Bioorg. Med. Chem. 2002, 12, 1571-1573.
25. The use of 2,5-thienylamidine P1 as a benzamidine surrogate for thrombin inhibitors was described in our previous communications; see ref 11 and the following. Lee, K.; Hwang, S. Y.; Yun, M.; Kim, D. S. Potent and Efficacious Thienylamindine-Incorporated Thrombin Inhibitors. Bioorg. Med. Chem. 1998, 6, 1683-1686. This P1 element was also utilized by other research groups; see the following. Reiner, J. E.; Sieve, D. V.; Araldi, G.-L.; Cui, J. J.; Ho, J. Z.; Reddy, K. M.; Mamedova, L.; Vu, P. H.; Lee, K.-S. S.; Minami, N. K.; Gibson, T. S.; Anderson, S. M.; Brabury, A. E.; Nolan, T. G.; Semple, J. E. Non-Covalent Thrombin Inhibitors Featuring P3-Heterocycles with P1-Monocyclic Arginine Surrogates. Bioorg. Med. Chem. 2002, 12, 1203-1208. Lange, U. E. W.; Zechel, C. Solid-Phase Synthesis of Thrombin Inhibitors. Bioorg. Med. Chem. 2002, 12, 1571-1573.
26. The use of 2,5-thienylamidine P1 as a benzamidine surrogate for thrombin inhibitors was described in our previous communications; see ref 11 and the following. Lee, K.; Hwang, S. Y.; Yun, M.; Kim, D. S. Potent and Efficacious Thienylamindine-Incorporated Thrombin Inhibitors. Bioorg. Med. Chem. 1998, 6, 1683-1686. This P1 element was also utilized by other research groups; see the following. Reiner, J. E.; Sieve, D. V.; Araldi, G.-L.; Cui, J. J.; Ho, J. Z.; Reddy, K. M.; Mamedova, L.; Vu, P. H.; Lee, K.-S. S.; Minami, N. K.; Gibson, T. S.; Anderson, S. M.; Brabury, A. E.; Nolan, T. G.; Semple, J. E. Non-Covalent Thrombin Inhibitors Featuring P3-Heterocycles with P1-Monocyclic Arginine Surrogates. Bioorg. Med. Chem. 2002, 12, 1203-1208. Lange, U. E. W.; Zechel, C. Solid-Phase Synthesis of Thrombin Inhibitors. Bioorg. Med. Chem. 2002, 12, 1571-1573.
27. (a) Teger-Nilsson, A. C.; Gyzander, E.; Anderson, S.; Englund, M.; Mattson, C.; Ulvinger, J. C.; Gustafsson, D. In Vitro Properties of Inogatran, a Selective Low Molecular Weight Inhibitor of Thrombin. Thromb. Haemostasis 1997, 73, 1633.
28. (b) Preville, P.; He, J. X.; Tarazi, M.; Siddiqui, M. A.; Cody, W. L.; Doherty, A. M. An Efficient Preparation of the Potent and Selective Pseudopeptide Thrombin Inhibitor, Inogatran. Bioorg. Med. Chem. 1997, 7, 1563-1566.
29. (a) Adang, A. E. P.; de Man, A. P. A.; Vogel, G. M. T.; Grootenhuis, P. D. J.; Smit, M. J.; Peters, C. A. M.; Visser, A.; Rewinkel, J. B. M.; van Dinther, T.; Lucas, H.; Kelder, J.; van Aelst, S.; Meiuleman, D. G.; van Boeckel, C. A. A. Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics. J. Med. Chem. 2002, 45, 4419-4432.
30. (b) Danilewicz, J. C.; Abel, S. M.; Brown, A. D.; Fish, P. V.; Hawkeswood, E.; Holland, S. J.; James, K.; McElroy, A. B.; Overington, J.; Powling, M. J.; Rance, D. J. Design of Selective Thrombin Inhibitors Based on the (R)-PhePro-Arg Sequence. J. Med. Chem. 2002, 45, 2432-2453.
31. (c) Hauel, N. H.; Nar, H.; Priepke, H.; Ries, U.; Stassen, J.-M.; Wienen, W. Structure-Based Design of Novel Thrombin Inhibitors. J. Med. Chem. 2002, 45, 1757-1766.
32. (d) Wiley, M. R.; Weir, L. C.; Bliggs, S. L.; Chirgadze, N. Y.; Clawson, D.; Gifford-Moor, D. S.; Smith, G. F.; Vasudevan, V.; Zornes, L. L.; Klimkowski, V. J. The Design of Potent, Selective, Non-covalent, Peptide Thrombin Inhibitors Utilizing Imidazole as a S1 Binding Element. Bioorg. Med. Chem. Lett. 1999, 9, 2767-2772.
33. (e) Adang, A. E. P.; Lucas, H.; de Man, A. P. A.; Engh, R. A.; Grootenhuis, P. D. J. Novel Acylguanidine Containing Thrombin Inhibitors with Reduced Basicity at the P1 Moiety. Bioorg. Med. Chem. Lett. 1998, 8, 3603-3608.
34. (a) Gustafson, D.; Antonsson, T.; Bylund, R.; Eriksson, U.; Gyzander, E. ; Nilsson, I.; Elg, M.; Mattsson, C.; Deinum, J.; Pehrsson, S.; Karlsson, O.; Nilsson, A.; Sorensen, H. Effects of Melagatran, a New Low Molecular Weight Thrombin Inhibitor, on Thrombin and Fibrinolytic Enzymes. Thromb. Haemostasis 1997, 78, 1286-1292.
35. (b) Eriksson, B. I.; Carlsson, S.; Halvarsson, M.; Risberg, B.; Mattsson, C. Antithrombotic Effect of Two Low Molecular Weight Thrombin Inhibitors and a Low Molecular Heparin in a Caval Vein Thrombosis Model in the Rat. Thromb. Haemostasis 1997, 78, 1404-1407.
36. (c) Sorbera, L. A.; Bayes, M.; Castaner, J.; Silvestre, J. Melagatran and Ximelagatran. Drugs Future 2001, 26, 1155-1170.
37. Adang et al. also reported different oral bioavailability profiles among structurally similar carboxymethyl derivatives of tripeptidic thrombin inhibitors (see ref 17a).
38. Details of crystallogarphic data will be published elsewhere.
39. Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.; Sardharwala, T. A. Synth. Commun. 1996, 26, 4351.
40. Schacht, A. L.; Smith, G. F.; Wiley, M. F. Antithrombotic Agents. U.S. Patent 5,710,130, 1998.
41. Ewing, W. R.; Becker, M. R.; Manetta, V. A.; Davis, R. S.; Pauls, H. W.; Mason, H.; Choi-Sledeski, Y. M.; Green, D.; Cha, D.; Spada, A. P.; Cheney, D. L.; Mason, J. S.; Maignan, S.; Guilloteau, J.-P.; Brown, K.; Colussi, D.; Bentley, R.; Bostwick, J.; Kasiewski, C. J.; Morgan, S. R.; Leadley, R. J.; Dunwiddie, C. T.; Perrone, M. H.; Chu, V. Design and Structure-Activity Relationships of Potent and Selective Inhibitors of Blood Coagulation Factor Xa. J. Med. Chem. 1999, 42, 3557-3571.
42. Videnov, G.; Kaiser, D.; Kempter, C.; Jung, G. Synthesis of Naturally Occurring, Conformationally Restricted Oxazole- and Thiazole-Containing Di- and Tripeptide Mimics. Angew. Chem., Int. Ed. Engl. 1996, 35, 1503-1506.
43. Lee, K.; Hwang, S. Y.; Hong, S. W.; Hong, C. Y.; Lee, C.-S.; Shin, Y.; Kim, S.; Yun, M.; Yoo, Y. J.; Kang, M.; Oh, Y. S. Structural Modification of an Orally Active Thrombin Inhibitor, LB30057: Replacement of the D-Pocket-Binding Naphthyl Moiety. Bioorg. Med. Chem. 1998, 6, 869-876.
44. Millet, J.; Theveniaux, J.; Brown, N. L. The Venous Antithrombotic Effect of LF 1351 in the Rat following Oral Administration. Thromb. Haemostasis 1992, 67, 176-179.