کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2487501 | 1114419 | 2008 | 16 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Stability and Hydrolysis Kinetics of Spirosuccinimide type Inhibitors of Aldose Reductase in Aqueous Solution and Retardation of Their Hydrolysis by the Target enzyme
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موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
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چکیده انگلیسی
The stability and the hydrolysis kinetics of spirosuccinimide type aldose reductase (AR) inhibitors, SXâ3030 (racemate) and its optical enantiomers (Râ and Sâisomers), were investigated in aqueous solution. The hydrolysis followed pseudoâfirstâorder kinetics and showed significant pH dependence. Maximum solution stability was observed below pH 2.4, whereas the hydrolysis was gradually catalyzed by hydroxide ion at neutral to alkaline pH while the compounds exhibiting moderate pHâindependent stability at acidic to neutral conditions (pH 4-7) to enable oral administration. A pK of 3.7 was obtained from the pHârate profile, but this kinetically derived pK is approximately 2 pH units below the pK of the parent compounds, suggesting the presence of an acidic intermediate involved in the hydrolysis process. These findings, together with structural analysis, support the notion that the hydrolysis would proceed via nucleophilic attack of a water molecule or hydroxide ion on the scissile carbonyl bond of the succinimide ring to form a succinamic acid intermediate that has a βâketo acid structure, followed by decarboxylation to give a racemized succinimide ringâopened product. On the other hand, the interconversion of the Râ and Sâisomers did not occur during hydrolysis; however, the hydrolysis of the Râisomer was markedly suppressed by the target enzyme AR whereas that of the Sâisomer was not, indicating a high degree of complementarity of interacting surfaces between the Râisomer and the enzyme. The results in the present study could provide useful clues for facilitating the appropriate stabilization strategies as well as for evaluating the pharmacological effects on target tissues in vivo, and suggested that the Râisomer may be a suitable candidate as AR inhibitor. © 2007 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 97:1468-1483, 2008
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 97, Issue 4, April 2008, Pages 1468-1483
Journal: Journal of Pharmaceutical Sciences - Volume 97, Issue 4, April 2008, Pages 1468-1483
نویسندگان
Masuo Kurono, Akira Itogawa, Hideto Noguchi, Mitsugu Sanjoba,