Search

Your search keyword '"Tim J. Allison"' showing total 2 results
Start Over Author "Tim J. Allison"
2 results on '"Tim J. Allison"'

1. Discovery of aminoheterocycles as a novel β-secretase inhibitor class: pH dependence on binding activity part 1

Author

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
Full Text
View/download PDF

2. A conformational constraint improves a β-secretase inhibitor but for an unexpected reason

Author

Ashley Nomland, Dennis Colussi, Tim J. Allison, Samuel L. Graham, M. Katharine Holloway, Pablo De Leon, Hemaka A. Rajapakse, Hong Zhu, Sharie J. Haugabook, Sanjeev Munshi, Shawn J. Stachel, Ivory D. Hills, Beth Pietrak, and Dawn Toolan

Subjects
Molecular model, Stereochemistry, Clinical Biochemistry, Molecular Conformation, Pharmaceutical Science, Crystallography, X-Ray, Biochemistry, Hydrophobic effect, Catalytic Domain, Drug Discovery, Amyloid precursor protein, Humans, Protease Inhibitors, ATP Binding Cassette Transporter, Subfamily B, Member 1, Molecular Biology, chemistry.chemical_classification, Binding Sites, biology, Bicyclic molecule, Chemistry, Organic Chemistry, Imidazoles, Small molecule, Protein Structure, Tertiary, Enzyme, Enzyme inhibitor, Drug Design, biology.protein, Molecular Medicine, Efflux, Amyloid Precursor Protein Secretases
Abstract

During our ongoing efforts to develop a small molecule inhibitor targeting the β-amyloid cleaving enzyme (BACE-1), we discovered a class of compounds bearing an aminoimidazole motif. Initial optimization led to potent compounds that have high Pgp efflux ratios. Crystal structure-aided design furnished conformationally constrained compounds that are both potent and have relatively low Pgp efflux ratios. Computational studies performed after these optimizations suggest that the introduction of the constraint enhances potency via additional hydrophobic interactions rather than conformational restriction.

Published
2009
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results