Design, synthesis, and tripeptidyl peptidase II inhibitory activity of a novel series of (S)-2,3-dihydro-2-(4-alkyl-1H-imidazol-2-yl)-1H-indoles
Autor: | Hans De Winter, Tamara A. Miskowski, Daniëlle C G Peeters, Diane A. Gauthier, Henry J. Breslin, Michael Joseph Kukla, William H Leister, Maria V. F. Somers, Peter Walter Maria Roevens |
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Rok vydání: | 2002 |
Předmět: |
Models
Molecular Indoles Serine Proteinase Inhibitors Stereochemistry medicine.drug_class medicine.medical_treatment Carboxamide Chemical synthesis Aminopeptidases Structure-Activity Relationship Drug Discovery medicine Structure–activity relationship Enzyme Inhibitors Dipeptidyl-Peptidases and Tripeptidyl-Peptidases Serine protease Protease biology Chemistry Serine Endopeptidases Imidazoles Tripeptidyl peptidase II Active site Stereoisomerism Enzyme inhibitor biology.protein Molecular Medicine |
Zdroj: | Journal of medicinal chemistry. 45(24) |
ISSN: | 0022-2623 |
Popis: | Butabindide, 1, was previously reported as a potent inhibitor (IC50 = 7 nM) of the serine protease enzyme tripeptidyl peptidase II (TPPII), an endogenous protease that degrades cholecystokinin-8 (CCK-8). We found that 1 has some inherent chemical instability, yielding diketopiperazine 2 fairly readily under mimicked physiological conditions. We therefore prepared imidazoles 3, which are void of 1's inherent instability, and have found that our novel analogues maintained comparable TPPII inhibitory activity (e.g.,for 3c, IC50 = 4 nM) as 1. |
Databáze: | OpenAIRE |
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