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Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Sep 01; Vol. 22 (17), pp. 5460-5. Date of Electronic Publication: 2012 Jul 20. - Publication Year :
- 2012
-
Abstract
- Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13 nM) and cellular (IC(50)=21 nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Alzheimer Disease drug therapy
Alzheimer Disease enzymology
Amyloid Precursor Protein Secretases chemistry
Amyloid Precursor Protein Secretases metabolism
Catalytic Domain
Cell Line, Tumor
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors chemical synthesis
Humans
Models, Molecular
Pyrazoles chemical synthesis
Pyrazoles chemistry
Pyrazoles pharmacology
Quinazolines chemical synthesis
Structure-Activity Relationship
Thiazoles chemical synthesis
Thiazoles chemistry
Thiazoles pharmacology
Amyloid Precursor Protein Secretases antagonists & inhibitors
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Quinazolines chemistry
Quinazolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 22
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 22863204
- Full Text :
- https://doi.org/10.1016/j.bmcl.2012.07.043