Novel Morpholinone-Based ?-Phe-Pro-Arg Mimics as Potential Thrombin Inhibitors: Design, Synthesis, and X-ray Crystal Structure of an Enzyme Inhibitor Complex
| Autor: | Anders Dahlgren, Per Johansson, Ingemar Kvarnström, Djordje Musil, Ingemar Nilsson, Bertil Samuelsson |
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| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular Molecular model medicine.drug_class Stereochemistry Morpholines Clinical Biochemistry Molecular Conformation Pharmaceutical Science Carboxamide Tripeptide Crystallography X-Ray Biochemistry Chemical synthesis Structure-Activity Relationship Thrombin Drug Discovery medicine Enzyme Inhibitors Structural motif Molecular Biology biology Chemistry Molecular Mimicry fungi Organic Chemistry food and beverages Enzyme inhibitor Drug Design biology.protein Molecular Medicine Oligopeptides medicine.drug Discovery and development of direct thrombin inhibitors |
| Zdroj: | Bioorganic & Medicinal Chemistry. 10:1829-1839 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/s0968-0896(02)00023-8 |
| Popis: | A morpholinone structural motif derived from D(+)- and L(-)-malic acid has been used as a mimic of D-Phe-Pro in the thrombin inhibiting tripeptide D-Phe-Pro-Arg. In place of Arg the more rigid P1 truncated p-amidinobenzylamine (Pab) or 2-amino-5-aminomethyl-3-methyl-pyridine have been utilized. The synthetic strategy developed readily delivers these novel thrombin inhibitors used to probe the alpha-thrombin inhibitor binding site. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC(50) of 720 nM. The X-ray crystal structure of this candidate co-crystallized with alpha-thrombin is discussed. |
| Databáze: | OpenAIRE |
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