1. Design and synthesis of potent beta-secretase (BACE1) inhibitors with P1' carboxylic acid bioisosteres.
- Author
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Kimura T, Hamada Y, Stochaj M, Ikari H, Nagamine A, Abdel-Rahman H, Igawa N, Hidaka K, Nguyen JT, Saito K, Hayashi Y, and Kiso Y
- Subjects
- Alzheimer Disease drug therapy, Amyloid Precursor Protein Secretases, Crystallography, X-Ray, Drug Evaluation, Preclinical, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Models, Molecular, Molecular Structure, Oligopeptides chemistry, Oligopeptides pharmacology, Stereoisomerism, Structure-Activity Relationship, Carboxylic Acids chemistry, Drug Design, Endopeptidases drug effects, Enzyme Inhibitors chemical synthesis, Oligopeptides chemical synthesis
- Abstract
Recently, we reported potent and small-sized beta-secretase (BACE1) inhibitors KMI-420 and KMI-429 in which we replaced the Glu residue at the P4 position of KMI-260 and KMI-360, respectively, with a 1H-tetrazole-5-carbonyl DAP (L-alpha,beta-diaminopropionic acid) residue. At the P1' position, these compounds contain one or two carboxylic acid groups, which are unfavorable for crossing the blood-brain barrier. Herein, we report BACE1 inhibitors with P1' carboxylic acid bioisosteres in order to develop practical anti-Alzheimer's disease drugs. Among them, tetrazole ring-containing compounds, KMI-570 (IC50=4.8 nM) and KMI-684 (IC50=1.2 nM), exhibited significantly potent BACE1 inhibitory activities.
- Published
- 2006
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