کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1366423 | 981590 | 2007 | 4 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Structure–activity relationship, kinetic mechanism, and selectivity for a new class of ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitors Structure–activity relationship, kinetic mechanism, and selectivity for a new class of ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitors](/preview/png/1366423.png)
3-Amino-2-keto-7H-thieno[2,3-b]pyridin-6-one derivatives were discovered as moderately potent inhibitors of ubiquitin C-terminal hydrolase-L1 (UCH-L1) utilizing an assay that measures hydrolysis of the fluorogenic substrate Ub-AMC. SAR studies revealed that both the carboxylate at the 5-position and the 6-pyridone ring were critical for inhibitory activity. Furthermore, activity was dependent on the nature of the ketone substituent at the 2-position, with 4-Me-Ph and 2-naphthyl being best. Kinetic mechanism studies revealed that these compounds were uncompetitive inhibitors of UCH-L1, binding only to the Michaelis-complex and not to free enzyme. The active compounds were selective for UCH-L1, exhibiting neither inhibition of other cysteine hydrolases (e.g., UCH-L3, papain, isopeptidase T, caspase-3, and tissue transglutaminase) nor cytotoxicity in N2A cells.
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Journal: Bioorganic & Medicinal Chemistry Letters - Volume 17, Issue 13, 1 July 2007, Pages 3729–3732