Liver-Targeted Small-Molecule Inhibitors of Proprotein Convertase Subtilisin/Kexin Type 9 Synthesis.
Angew Chem Int Ed Engl
; 56(51): 16218-16222, 2017 12 18.
Article
em En
| MEDLINE
| ID: mdl-29073340
ABSTRACT
Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesteraseâ
1. The synthesis of select tetrazole prodrugs was crucial. A cell-free inâ
vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. Inâ
vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18 F-isotopologue validated our liver-targeting approach.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Bibliotecas de Moléculas Pequenas
/
Pró-Proteína Convertase 9
/
Inibidores de PCSK9
/
Fígado
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article