Design and Synthesis of a Series of Potent and Orally Bioavailable Noncovalent Thrombin Inhibitors That Utilize Nonbasic Groups in the P1 Position
| Autor: | Adel M. Naylor-Olsen, John T. Sisko, K.J. Stauffer, Elizabeth P. Baskin, Stephen F. Brady, C. M. Cooper, Maria T. Stranieri, Julie A. Krueger, K B Dancheck, Thomas J. Tucker, Elizabeth A. Lyle, J.J. Lynch, I.-W. Chen, Bobby J. Lucas, Jacquelynn J. Cook, William C. Lumma, S. D. Lewis, J. P. Vacca, Stephen J. Gardell, Marie A. Holahan, Youwei Yan |
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| Rok vydání: | 1998 |
| Předmět: |
Models
Molecular Stereochemistry medicine.drug_class Molecular Conformation Administration Oral Biological Availability Carboxamide Crystallography X-Ray Chemical synthesis Structure-Activity Relationship Dogs Thrombin Fibrinolytic Agents In vivo Drug Discovery medicine Animals Structure–activity relationship Computer Simulation Cyclohexylamines Binding Sites Molecular Structure biology Chemistry Active site Hydrogen Bonding Dipeptides Rats Macaca fascicularis Drug Design Lipophilicity biology.protein Molecular Medicine Resins Plant medicine.drug Discovery and development of direct thrombin inhibitors |
| Zdroj: | Journal of Medicinal Chemistry. 41:3210-3219 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site. |
| Databáze: | OpenAIRE |
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