التفاصيل البيبلوغرافية
| العنوان: |
Synthesis, stability, biochemical and pharmacokinetic properties of a new potent and selective 4-oxo-ββ-lactam inhibitor of human leukocyte elastase. |
| المؤلفون: |
Mulchande, Jalmira, Simões, Sandra I., Gaspar, Maria M., Eleutério, Carla V., Oliveira, Rudi, Cruz, Maria E.M., Moreira, Rui, Iley, Jim |
| المصدر: |
Journal of Enzyme Inhibition & Medicinal Chemistry; Apr2011, Vol. 26 Issue 2, p169-175, 7p |
| مصطلحات موضوعية: |
PHARMACOKINETICS, LACTAMS, LEUCOCYTE elastase, NEUTROPHILS, SERINE proteinases, INFLAMMATION, ACYLATION, HYDROLYSIS, HYDROGEN-ion concentration, PHOSPHATES, HIGH performance liquid chromatography, MAGNETIC resonance imaging |
| مستخلص: |
The 4-oxo-ββ-lactams (azetidine-2,4-diones) are potent acylating agents of the human leukocyte elastase (HLE), a neutrophil serine protease that plays a key role in several inflammatory diseases. A novel 4-oxo-ββ-lactam containing a N-(4-(phenylsulphonylmethyl)phenyl) group, 3, was designed as a potential mechanism-based inhibitor capable of undergoing elimination of phenylsulphinate upon Ser-195 acylation. Compound 3 was found to be a potent slow-tight binding inhibitor of HLE, presenting a remarkable second-order rate constant of 1.46 ×× 106 M−−1s−−1 and displaying selectivity over the proteinase 3 and cathepsin G. However, liberation of phenylsulphinate was not observed in the hydrolysis of 3 in both pH 7.4 phosphate buffer and human plasma. The Cmax values of 1207 μμg/total blood, 179 μμg/g spleen and 106 μμg/g lung were determined by HPLC, following a single 30 mg/kg dose of 3 given intraperitoneally to NMRI mice, suggesting that the inhibitor distributes well into tissues. Although being a powerful selective inhibitor of HLE, 4-oxo-ββ-lactam 3 has a limited stability, being susceptible to off-target reactions (plasma and liver enzymes). [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |