Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure.
Bioorg Med Chem
; 52: 116517, 2021 12 15.
Article
em En
| MEDLINE
| ID: mdl-34800875
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 ß-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.
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Base de dados:
MEDLINE
Assunto principal:
Peptídeos
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Ácido Aspártico Endopeptidases
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Reagentes de Ligações Cruzadas
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Compostos Macrocíclicos
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Etilaminas
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Secretases da Proteína Precursora do Amiloide
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article