Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors
| Autor: | James C. Barrow, Kenneth E. Rittle, Lawrence C. Kuo, Audrey A. Wallace, Bobby J. Lucas, George F. Lundell, Beth Pietrak, Harold G. Selnick, Rebecca B. White, S. Dale Lewis, Franklin C. Clayton, Christina L. Newton, Youwei Yan, Janetta M. Pellicore, Daniel R. McMasters, Peter D. Williams, Philippe G. Nantermet, Kenneth J. Stauffer, Bradley K. Wong, Cynthia Miller-Stein, Kristen L. Glass, Julie A. Krueger, Mary Beth Young, Jacquelynn J. Cook, Joseph P. Vacca, Dennis L. Bohn |
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| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Benzylamines Molecular model Stereochemistry medicine.drug_class Pyridines Tetrazoles Carboxamide Chemical synthesis chemistry.chemical_compound Structure-Activity Relationship Thrombin Heterocyclic Compounds Drug Discovery Thiadiazoles medicine Tetrazole Binding Sites Chemistry Aryl Triazoles Pyrazines Lactam Molecular Medicine medicine.drug Discovery and development of direct thrombin inhibitors |
| Zdroj: | Journal of medicinal chemistry. 47(12) |
| ISSN: | 0022-2623 |
| Popis: | In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns. |
| Databáze: | OpenAIRE |
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