Structure–activity relationship study of BACE1 inhibitors possessing a chelidonic or 2,6-pyridinedicarboxylic scaffold at the P2 position
| Autor: | Koushi Hidaka, Moe Yamasaki, Kenji Suzuki, Yoshio Hamada, Diganta Sarma, Ryoji Yamaguchi, Yoshiaki Kiso, Shoichi Ishiura, Tomoya Nakanishi, Hiroko Ohta |
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| Rok vydání: | 2014 |
| Předmět: |
Scaffold
Pyridines Isostere Stereochemistry Clinical Biochemistry Pharmaceutical Science Biochemistry Protein Structure Secondary Structure-Activity Relationship In vivo mental disorders Drug Discovery Aspartic Acid Endopeptidases Humans Moiety Structure–activity relationship Enzyme Inhibitors Picolinic Acids Molecular Biology Pyrans chemistry.chemical_classification Binding Sites Chemistry Organic Chemistry Substrate (chemistry) Protein Structure Tertiary Amino acid HEK293 Cells Enzyme Molecular Medicine Amyloid Precursor Protein Secretases |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 24:618-623 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2013.12.007 |
| Popis: | We have previously reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. While these inhibitors exhibited potent activities in enzymatic and cellular assays (KMI-429 in particular inhibited Aβ production in vivo), these inhibitors contained some natural amino acids that seemed to be required to improve enzymatic stability in vivo and permeability across the blood–brain barrier, so as to be practical drug. Recently, we synthesized non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold at the P2 position. Herein we report the SAR study of BACE1 inhibitors possessing this heterocyclic scaffold, a chelidonic or 2,6-pyridinedicarboxylic moiety. |
| Databáze: | OpenAIRE |
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