Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region.
Bioorg Med Chem
; 26(5): 1035-1049, 2018 03 01.
Article
em En
| MEDLINE
| ID: mdl-29398442
ABSTRACT
Pyroglutamate-modified amyloid ß peptides (pGlu-Aß) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aß peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer's disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region. In the present study, we focused on the structure activity relationship (SAR) of analogues with modifications in the D-region and evaluated their biological activity. Most compounds in this series exhibited potent activity in vitro, and our SAR analysis and the molecular docking studies identified compound 202 as a potential candidate because it forms an additional hydrophobic interaction in the hQC active site. Overall, our study provides valuable insights into the Arg-mimetic pharmacophore that will guide the design of novel QC inhibitors as potential treatments for AD.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aminoaciltransferases
/
Inibidores Enzimáticos
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2018
Tipo de documento:
Article