In vitro evaluation and crystallographic analysis of a new class of selective, non-amide-based thrombin inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 13, 1998, Pages 1595-1600

  Lu, Tianbao ^a   Tomczuk, Bruce ^a   Illig, Carl R ^a   Bone, Roger ^a   Murphy, Larry ^a   Spurlino, John ^a   Salemme, F Raymond ^a   Soll, Richard M ^a  

^a Eagleview Corporate Center   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARGATROBAN; CVS 1123; EFEGATRAN; NAPSAGATRAN; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CRYSTAL STRUCTURE; DISSOCIATION CONSTANT; DRUG BINDING SITE; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; ENZYME INHIBITION; HYDROGEN BOND; STRUCTURE ACTIVITY RELATION;

EID: 0032493412     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00290-X     Document Type: Article

References (15)

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4. 4. For an example of the influence of guanidino replacements in an aminoacid-based scaffold, see: Misra, R. J.; Kelly, Y. F.; Brown, B.; Roberts, D. G. M.; Chong, S.; Seiler, S. M. Bioorg. Med. Chem. Lett. 1994, 4, 2165.
5. 5. For an informative discussion on the necessity for lipophilicity on inhibitors based on a tripeptide backbone, see: Tucker, T. J.; Lumma, W. C.; Lewis, S. D.; Gardell, S. J.; Lucas, B. J.; Basking, E. P.; Woltmann, R.; Lynch, J. J.; Lyle, E. A.; Appleby, S. D.; Chen, I-W.; Dancheck, K. B.; Vacca, J. P. J. Med. Chem. 1997, 40, 1565.
6. 6. Graybill, T. L.; Agrafiotis, D. K.; Bone, R.; Illig, C. R.; Jaeger, E. P.; Locke, K. T.; Lu, T.; Salvino, J. M.; Soll, R. M.; Spurlino, J. C.; Subasinghe, N.; Tomczuk, B. E.; Salemme, F. R. In Molecular Diversity and Combinatorial Chemistry, Libraries and Drug Discovery; Chaiken, I. M.; Janda, K. D., Eds.; American Chemical Society, Washington, 1996; 16.
7. 7. Lu, T.; Illig, C. R.; Tomczuk, B.; Soll, R. M.; Subasinghe, N. L.; Bone, R. F. WO 97/11693, 1997.
8. 8. Mitsunobu, O. Synthesis 1981, 1.
9. m values for each enzyme were: succinyl-Ala-Ala-Pro-Arg-p-nitroanilide, 100 μM and 320 μM for human α-thrombin; benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide, 100 μM and 2300 μM for human factor Xa; carbobenzyloxy-Phe-Val-Arg-p-nitroanilide, 170 μM and 190 μM for human urokinase; tosyl-Gly-Pro-Lys-p-nitroanilide, 100 μM and 690 μM for human plasmin; benzoyl-Phe-Val-Arg-p-nitroanilide, 100 μM and 160 μM for bovine trypsin; suc-Ala-Ala-Pro-Phe-p-nitroanilide, 100 μM and 60 μM for bovine chymotrypsin; sue-Ala-Ala-Pro-Val-p-nitroanilide, 100 μM and 2600 μM for human elastase.
10. 10. Bone, R. B.; Lu, T.; Illig, C. R.; Soll, R. M.; Spurlino, J. C. J. Med. Chem. in press.
11. 11. Engh, R. A.; Brandstetter, H.; Sucher, G.; Eichinger, A.; Baumann, U.; Bode, W.; Huber, R.; Poll, T.; Rudolph, R.; von der Saal, W. Structure, 1996, 4, 1353.
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13. 13. Illig, C.; Eisennagel, S.; Bone, R.; Radzicka, A.; Murphy, L.; Randle, T.; Spurlino, J.; Jaeger, E.; Salemme, F. R.; Soll, R. M. Med. Chem. Res., in press.
14. 14. Bone, R.; Agard, D. A. Methods in Enzymology 1991, 202, 643.
15. 15. Crystallographic data for 5:R = 0.18 at 2.2 Å resolution; 17R = 0.20 at 1.9 Å resoluton; 14 R = 0.205 at 2.0 Å resolution.