Combinatorial assembly, traceless generation and in situ evaluation of inhibitors for therapeutically relevant serine proteases.
Bioorg Chem
; 121: 105676, 2022 04.
Article
em En
| MEDLINE
| ID: mdl-35202850
ABSTRACT
A combinatorial method was devised and applied for the design and identification of substrate-analogue inhibitors of therapeutically relevant serine proteases, such as thrombin and factor Xa. We conceptualized imino acid derived diketomorpholines as generally applicable key intermediates prepared through solid-phase synthesis and prone to be cleaved with primary amines in a traceless fashion. The approach led to a compound library whose members were prepared under bioassay-compatible conditions and directly subjected to the in situ evaluation, allowing a fast prediction of hit compounds. Highly active inhibitors for serine proteases of the coagulation cascade have been identified. The most potent dual inhibitor, 16K, has a binding affinity of 23.9â¯nM to thrombin and 32.8â¯nM to factor Xa.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Trombina
/
Fator Xa
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article