Synthesis of a Series of Potent and Orally Bioavailable Thrombin Inhibitors That Utilize 3,3-Disubstituted Propionic Acid Derivatives in the P3 Position
Autor: | E P Baskin, Adel M. Naylor-Olsen, C. M. Cooper, Appleby Sd, J. P. Vacca, K B Dancheck, Stephen J. Gardell, Elizabeth A. Lyle, William C. Lumma, I.-W. Chen, John T. Sisko, S. D. Lewis, Julie A. Krueger, R Woltmann, J.J. Lynch, Bobby J. Lucas, Thomas J. Tucker |
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Rok vydání: | 1997 |
Předmět: |
Magnetic Resonance Spectroscopy
medicine.drug_class Stereochemistry Administration Oral Biological Availability Carboxamide Spectrometry Mass Fast Atom Bombardment Chemical synthesis Dogs Thrombin Drug Discovery medicine Animals Moiety biology Chemistry Rats Bioavailability Enzyme inhibitor Lipophilicity biology.protein Molecular Medicine Propionates medicine.drug Discovery and development of direct thrombin inhibitors |
Zdroj: | Journal of Medicinal Chemistry. 40:3687-3693 |
ISSN: | 1520-4804 0022-2623 |
Popis: | As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a,b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P 3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P 3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl 3 -induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a. |
Databáze: | OpenAIRE |
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