Metabolism-based identification of a potent thrombin receptor antagonist

Journal of Medicinal Chemistry

Volumn 50, Issue 1, 2007, Pages 129-138

  Clasby, Martin C ^a   Chackalamannil, Samuel ^a   Czarniecki, Michael ^a   Doller, Dario ^a   Eagen, Keith ^a   Greenlee, William ^a   Kao, Grace ^a   Lin, Yan ^a   Tsai, Hsingan ^a   Xia, Yan ^a   Ahn, Ho Sam ^a   Agans Fantuzzi, Jacqueline ^a   Boykow, George ^a   Chintala, Madhu ^a   Foster, Carolyn ^a   Smith Torhan, April ^a   Alton, Kevin ^a   Bryant, Matthew ^a   Hsieh, Yunsheng ^a   Lau, Janice ^a   Palamanda, Jairam ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HIMBACINE; PROTEINASE ACTIVATED RECEPTOR; PROTEINASE ACTIVATED RECEPTOR 1; SCH 205831; THROMBIN RECEPTOR; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG METABOLISM; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INDUCTION; NONHUMAN; RAT; THROMBOCYTE AGGREGATION;

ANIMALS; BIOLOGICAL AVAILABILITY; CYTOCHROME P-450 ENZYME SYSTEM; FURANS; HETEROCYCLIC COMPOUNDS, 3-RING; HUMANS; MACACA FASCICULARIS; MICROSOMES, LIVER; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; PYRIDINES; RADIOLIGAND ASSAY; RATS; RECEPTORS, THROMBIN; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33846260165     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm061043e     Document Type: Article

References (34)

1. Coleman, R. W.; Marder, V. J.; Salzman, E. W.; Hirsh, J. Overview of hemostasis. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice; Coleman, R. W., Hirsch, J., Marder, V. J., Salzman, E. W., Eds.; Lippincott, Williams and Wilkins: Philadelphia, PA, 1994; pp 3-17.
2. Davie, E. W.; Fujikawa, K.; Kisiel, W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 1991, 30, 10363-10370.
3. De Caterina, R.; Sicari, R. Cellular effects of thrombin: Pharmacology of the receptor(s) in various cell types and possible development of receptor antagonists. Pharmacol. Res. 1993, 27, 1-19.
4. Shuman, M. A. Thrombin-cellular interactions. Ann. N.Y. Acad. Sci. 1986, 485, 228-239.
5. Harker, L. A. Pathogenesis of thrombosis. In Hematology; Williams, W. J., Beutler, E., Erslev, A. J., Lictman, M. A., Eds.; McGraw Hill: New York, 1990; pp 1559-1568.
6. Coughlin, S. R. Protease-activated Receptors. In Handbook of Cell Signaling; Bradshaw, R. A.; Dennis, E. A., Eds.; Elsevier: San Diego, 2004; Vol. 1, pp 167-171.
7. Coughlin, S. R. Protease-Activated Receptors in the Cardiovascular System. Cold Spring Harbor Symp. Quant. Biol. 2002, 67, 197-208.
8. Coughlin, S. R. Protease-Activated Receptors in Vascular Biology. Thromb. Haemostasis 2001, 86, 298-307.
9. Grand, R. J. A.; Turnell, A. S.; Grabham, P. W. Cellular consequences of thrombin-receptor activation. Biochem. J. 1996, 313, 353-368.
10. Coughlin, S. R. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemostasis 2005, 3, 1800-1814.
11. Coughlin, S. R. How the protease thrombin talks to cells. Proc. Natl. Acad. Sc. U.S.A. 1999, 96, 11023-11027.
12. Vu, T-K. H.; Hung, D. T.; Wheaton, V. I.; Coughlin, S.R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991, 64, 1057-1068.
13. Hung, D. T.; Vu, T.-H.; Nelken, N. A.; Coughlin, S. R. Thrombin-induced events in non-platelet cells are mediated by the unique proteolytic mechanism established for the cloned platelet thrombin receptor. J. Cell Biol. 1992, 116, 827-832.
14. Vu, T.-K. H.; Wheaton, V. I.; Hung, D. T.; Charo, I.; Coughlin, S. R. Domains specifying thrombin-receptor interaction. Nature 1991, 353, 674-677.
15. Nanevicz, T.; Ishii, M.; Wang, L.; Chen, M.; Chen, J.; Turck, C. W.; Cohen, F. E.; Coughlin, S. R. Mechanisms of thrombin receptor agonist specificity. Chimeric receptors and complementary mutations identify an agonist recognition site. J. Biol. Chem. 1995, 270, 21619-21625.
16. Chackalamannil, S. Thrombin Receptor (Protease-Activated Receptor-1) Antagonists as Potent Antithrombotic Agents with Strong Anti-platelet Effects. J. Med. Chem. 2006, 49, 5389-5403.
17. Seiler, S. M.; Bernatowicz, M. S. Peptide-derived protease-activated receptor-1 (PAR-1) antagonists. Curr. Med. Chem.; Cardiovasc. Hemat. Agents 2003, 1, 13.
18. Chackalamannil, S.; Xia, Y. Thrombin receptor (PAR-1) antagonists as novel antithrombotic agents. Expert Opin. Ther. Pat. 2006, 16, 493-505.
19. Chackalamannil, S.; Xia, Y.; Greenlee, W. J.; Clasby, M.; Doller, D.; Tsai, H.; Asberom, T.; Czarniecki, M.; Ahn. H.-S.; Boykow, G.; Foster, C.; Agans-Fantuzzi, J.; Bryant, M.; Lau, J.; Chintala, M. Discovery of Potent Orally Active Thrombin Receptor (Protease-Activated Receptor 1) Antagonists as Novel Antithrombotic Agents. J. Med. Chem. 2005, 48, 5884-5887.
20. Chackalamannil, S.; Asberom, T.; Xia, Y.; Doller, D.; Clasby, M. C.; Czarniecki, M. F. Preparation of himbacine analogs as thrombin receptor antagonists. U.S. Patent 6,063,847, May 16, 2000.
21. Zhang, H.-C.; Derian, C. K.; Andrade-Gordon, P.; Hoekstra, W. J.; McComsey, D. F.; White, K. B. Poulter, B. L.; Addo, M. F.; Cheung, W.-M.; Damiano, B. P.; Oksenberg, D.; Reynolds. E. E.; Pandey, A.; Scarborough, R. M.; Maryanoff, B. E. Discovery and Optimization of A Novel Series of Thrombin Receptor (PAR-1) Antagonists: Potent, Selective Peptide Mimetics Based on Indole and Indazole Templates. J. Med. Chem. 2001, 44, 1021-1024.
22. Kim, H.; Ahn, H.; Bryant, M.; Nomeir, A.; Chan, T.-M. Isolation and identification of the circulating major metabolites of the thrombin receptor antagonist SCH 205831 from rat liver microsomal incubations and rat bile using HPLC, LC/MS and LC/NMR. Manuscript in preparation.
23. McClellan, K.; Jarvis, B. Desloratadine. Drugs 2001, 61, 789-796.
24. Markham, A.; Wagstaff, A. J. Fexofenadine. Drugs 1998, 55, 269-274.
25. Singh, S. S. Preclinical pharmacokinetics: an approach towards safer and efficacious drugs. Curr. Drug Metab. 2006, 7, 165-182.
26. Nassar A-E.; F.; Kamel, A. M.; Clairmont, C. Improving the decision-making process in the structural modification of drug candidates: enhancing metabolic stability. Drug Discovery Today 2004, 9, 1020-1028.
27. 19 we obtained compounds that were enantiopure (>99%) by HPLC (CHIRALPAK AD, CHIRALCEL OD).
28. Lambert, J. B.; Liu, X. The β -effect of silicon in the orthogonal geometry. J. Organomet. Chem. 1996, 521, 203-210.
29. Shin, C.; Swenton. J. S. Use of protected β-bromocyclopentenones and β-bromocyclohexenones as β-acylvinyl anion equivalents. J. Org. Chem. 1982, 47, 2825-2832.
30. Four, P.; Guibe, F. Palladium-catalyzed reaction of tributyltin hydride with acyl chlorides. A mild, selective, and general route to aldehydes. J. Org. Chem. 1981, 46, 4439-4445.
31. Shih, C.; Fritzen, E. L.; Swenton, J. S. Photocycloaddition chemistry of 2-(trimethylsilyl)cyclopentenone and 5-(trimethylsilyl)uracil. The utility of a trimethylsilyl group as a removable directing group in photochemistry. J. Org. Chem. 1980, 45, 4462-4471.
32. Ahn, H.-S.; Foster, C.; Boykow, G.; Arik, L.; Smith-Torhan, A.; Hesk, D.; Chatterjee, M. Mol. Pharm. 1997, 51, 350-356. Assays were carried out in duplicate. Compounds of high interest were assayed multiple times (n > 5, SEM ± 20%).
33. Kinetic solubilities were measured for these compounds and were found to be ∼5 μM
34. Data not shown.