Discovery of novel N-acylpyrazoles as potent and selective thrombin inhibitors.
Eur J Med Chem
; 246: 114855, 2023 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-36462436
ABSTRACT
Direct oral anticoagulants (DOACs), which includes thrombin and factor Xa inhibitors, have emerged as the preferred therapeutics for thrombotic disorders, penetrating a market previously dominated by warfarin and heparin. This article describes the discovery and profiling of a novel series of N-acylpyrazoles, which act as selective, covalent, reversible, non-competitive inhibitors of thrombin. We describe in vitro stability issues associated with this chemotype and, importantly, demonstrate that N-acylpyrazoles successfully act in vivo as anticoagulants in basic thrombotic animal models. Crucially, this anticoagulant nature is unaccompanied by the higher bleeding risk profile that has become an undesirable characteristic of the DTIs and factor Xa inhibitors. We propose that the N-acylpyrazole chemotype shows intriguing promise as next-generation oral anticoagulants.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Trombose
/
Trombina
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2023
Tipo de documento:
Article