Discovery of Highly Selective, Potent, Covalent, and Orally Bioavailable Factor XIIa Inhibitors for the Treatment of Thrombo-Inflammation.
J Med Chem
; 67(13): 10946-10966, 2024 Jul 11.
Article
de En
| MEDLINE
| ID: mdl-38913497
ABSTRACT
Thrombo-inflammation is closely associated with a few severe cardiovascular and infectious diseases. Factor XIIa (FXIIa) in the intrinsic coagulation pathway plays a pivotal role in the development of thrombo-inflammation and its inhibition has emerged as a potential therapeutic approach for thrombo-inflammatory disorders. Nonetheless, as of now, few small-molecule FXIIa inhibitors have demonstrated notable effectiveness against thrombo-inflammation, with none progressing into clinical stages. Herein, we present potent, covalent, reversible, and selective small-molecule FXIIa inhibitors such as 4a and 4j obtained through structure-based drug design. Compounds 4a and 4j showed significant anticoagulation and substantial anti-inflammatory effects in vitro, coupled with exceptional plasma stability. Furthermore, in carrageenan-induced thrombosis models, 4a and 4j demonstrated remarkable dual antithrombotic and anti-inflammatory activity when administered orally. Compound 4j exhibited a favorable safety profile without obvious tissue toxicity in mice, suggesting its potential as an oral therapeutic option for thrombo-inflammation.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Thrombose
/
Facteur XIIa
Limites:
Animals
/
Humans
/
Male
Langue:
En
Journal:
J Med Chem
Sujet du journal:
QUIMICA
Année:
2024
Type de document:
Article
Pays d'affiliation:
Chine