1. Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure.
- Author
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Otani T, Hattori Y, Akaji K, and Kobayashi K
- Subjects
- Amyloid Precursor Protein Secretases metabolism, Aspartic Acid Endopeptidases metabolism, Cross-Linking Reagents chemical synthesis, Cross-Linking Reagents chemistry, Crystallography, X-Ray, Dose-Response Relationship, Drug, Ethylamines chemical synthesis, Ethylamines chemistry, Humans, Hydrophobic and Hydrophilic Interactions, Macrocyclic Compounds chemical synthesis, Macrocyclic Compounds chemistry, Models, Molecular, Molecular Structure, Peptides chemical synthesis, Peptides chemistry, Recombinant Proteins metabolism, Structure-Activity Relationship, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Cross-Linking Reagents pharmacology, Ethylamines pharmacology, Macrocyclic Compounds pharmacology, Peptides pharmacology
- Abstract
Based on the X-ray crystallography of recombinant BACE1 and a hydroxyethylamine-type peptidic inhibitor, we introduced a cross-linked structure between the P1 and P3 side chains of the inhibitor to enhance its inhibitory activity. The P1 and P3 fragments bearing terminal alkenes were synthesized, and a ring-closing metathesis of these alkenes was used to construct the cross-linked structure. Evaluation of ring size using P1 and P3 fragments with various side chain lengths revealed that 13-membered rings were optimal, although their activity was reduced compared to that of the parent compound. Furthermore, the optimal ring structure was found to be a macrocycle with a dimethyl branched substituent at the P3 β-position, which was approximately 100-fold more active than the non-substituted macrocycle. In addition, the introduction of a 4-carboxymethylphenyl group at the P1' position further improved the activity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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