1. Discovery of aminoheterocycles as a novel β-secretase inhibitor class: pH dependence on binding activity part 1
- Author
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Beth Pietrak, Hemaka A. Rajapakse, Dennis Colussi, Paul Zuck, Hong Zhu, Kristen L.G. Jones, Adam J. Simon, Samuel L. Graham, Shawn J. Stachel, M. Katharine Holloway, Diane M. Rush, Joseph P. Vacca, Amy S. Espeseth, Tim J. Allison, Ming-Tain Lai, Craig A. Coburn, Abigail Wolfe, and Sanjeev Munshi
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Plasma protein binding ,Crystallography, X-Ray ,Biochemistry ,Structure-Activity Relationship ,Heterocyclic Compounds ,Drug Discovery ,Hydrolase ,Amyloid precursor protein ,Structure–activity relationship ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,biology ,Ligand binding assay ,Organic Chemistry ,Hydrogen-Ion Concentration ,Enzyme binding ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,Protein Binding - Abstract
We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pK(a) of these inhibitors and the pH of the BACE-1 enzyme binding assay.
- Published
- 2009
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