Synthesis and structure-activity relationship of potent bicyclic lactam thrombin inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 7, 1999, Pages 913-918

  Bachand, Benoit ^a   DiMaio, John ^a   Siddiqui, M Arshad ^a  

^a Shire Canada   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ARGININE; THROMBIN INHIBITOR;

ARTICLE; BRAIN INFARCTION; CATALYSIS; DRUG POTENCY; DRUG SYNTHESIS; HEART INFARCTION; LIPOPHILICITY; LUNG EMBOLISM; PROTEIN DEGRADATION; STRUCTURE ACTIVITY RELATION; THROMBOGENESIS;

ANTITHROMBINS; BICYCLO COMPOUNDS; LACTAMS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0033526063     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00130-4     Document Type: Article

References (10)

1. 1. Presented at the 214th American Chemical Society Meeting (Las Vegas, NV, September 7-11, 1997)
2. 2. Hirsh, J.; Marder, V. J.; Saizman, E. W. Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 3rd Ed., Collman, R. W., Ed.; J. B. Lippincott: Philadelphia, 1994; p 1638.
3. 3. Edmunds, J. J.; Rapundalo, S. T.; Siddiqui, M. A. Ann. Rep. Med. Chem. 1996, 31, 51.
4. 4. Tapparelli, C.; Metternich, R.; Ehrhardt, C.; Cook, N. S. TiPS 1993, 14, 366.
5. 5. Meyers, Z. I.; Romo, D. Tetrahedron 1991, 46, 9503.
6. 6. The authors have deposited X-ray crystallographic data with the Cambridge Crystallographic Data Centre.
7. 7. The NMR spectrum of 14a is identical to a sample prepared using a different route, see: Siddiqui, M. A.; Préville, P.; Tarazi, M.; Warder S. E.; Eby P.; Gorseth, E.; Puumala, K.; DiMaio J. Tetrahedron Lett. 1997, 38, 8807.
8. 8. Compounds 15a,b were prepared according to the method shown below. (equation presented)
9. 9. For determination of binding affinities, see: Finkle, C. D.; St-Pierre, A.; Leblond, L.; Deschênes, I.; DiMaio, J.; Winocour, P. D. Thromb. Haemostasis. 1998, 79, 431.
10. 10. Since these inhibitors (e.g. 16f-16g) are derived from coupling of peptidomimetic acid with racemic thiazoloketoarginine (15a), corresponding hemiaminal isomers are expected to have four diastereoisomers. Moreover, nature of hemiaminal moiety is prone to undergo solvent dependant equilibration, thus the ratio of four diastereisomers is likely to vary from solvent to solvent. The fact that the two isomers (16f-16g), are stable entities and the ratio of isomers is solvent independant suggests that there are epimers at the arginine. However, each epimer undergoing equilibration to form hemiaminal under assay conditions can not be ruled out.