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SAR of tertiary carbinamine derived BACE1 inhibitors: role of aspartate ligand amine pKa in enzyme inhibition
- Source :
- Bioorganicmedicinal chemistry letters. 20(6)
- Publication Year :
- 2010
-
Abstract
- The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pKa of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Αβ production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.
- Subjects :
- Models, Molecular
Stereochemistry
Clinical Biochemistry
Cell
Pharmaceutical Science
Biochemistry
Catalysis
Structure-Activity Relationship
Drug Discovery
medicine
Potency
Aspartic Acid Endopeptidases
Humans
Amines
Enzyme Inhibitors
Molecular Biology
chemistry.chemical_classification
Aspartic Acid
biology
Organic Chemistry
Ligand (biochemistry)
Enzyme assay
Enzyme
medicine.anatomical_structure
chemistry
biology.protein
Molecular Medicine
Amine gas treating
Amyloid Precursor Protein Secretases
Cell culture assays
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 20
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....1fa021e12b11a8ad9927b76ea326038f