Exploration of orally available calpain inhibitors: Peptidyl α-ketoamides containing an amphiphile at P3 site
| Autor: | Hiroyuki Miyashita, Masayuki Nakamura, Yoshihisa Shirasaki, Masazumi Yamaguchi, Jun Inoue |
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| Rok vydání: | 2005 |
| Předmět: |
Magnetic Resonance Spectroscopy
Membrane permeability Stereochemistry Clinical Biochemistry Administration Oral Biological Availability Pharmaceutical Science Ether Cysteine Proteinase Inhibitors Biochemistry chemistry.chemical_compound Residue (chemistry) Drug Discovery Amphiphile Animals Humans Moiety Molecular Biology biology Calpain Organic Chemistry Diethylene glycol Amides Macaca fascicularis Solubility chemistry Enzyme inhibitor Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization biology.protein Molecular Medicine Female Caco-2 Cells Ethylene glycol |
| Zdroj: | Bioorganic & Medicinal Chemistry. 13:4473-4484 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2005.04.059 |
| Popis: | A novel series of dipeptidyl α-ketoamide derivatives with amphiphile was designed and synthesized as water-soluble calpain inhibitors. The introduction of amphiphiles at the P3 site increased water solubility without loss of membrane permeability and provided the oral available inhibitors. Extension of the ethylene glycol chain at the P3 site led to an improvement in persistence of plasma levels. In particular, introduction of a combination of a diethylene glycol methyl ether moiety at the P3 site, a phenylalanine residue at the P1 site and a cyclopropyl moiety at the P′ site was the most effective modification for an increase in plasma drug exposure. |
| Databáze: | OpenAIRE |
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