Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 18, Issue 24, Pages 8618-8629Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.10.006
Keywords
Chromen-based TACE inhibitors; Optimization; Docking; Quantitative structure-activity relationship; Genetic function approximation
Funding
- National Research Foundation [2009-0092966]
- Korean Research WCU [R31-2008-000-10086-0]
- Brain Korea 21 project, Republic of Korea
- National Research Foundation of Korea [2009-0092966] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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A series of coumarin based TACE inhibitors were designed to bind in S1' pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-alpha inhibition. Among these, 15l effectively inhibited the production of serum TNF-alpha by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1' pocket and the TACE inhibitory activity well. (C) 2010 Elsevier Ltd. All rights reserved.
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