Microscale Parallel Synthesis of Acylated Aminotriazoles Enabling the Development of Factor XIIa and Thrombin Inhibitors.
Acylation
Amitrole
/ chemical synthesis
Anticoagulants
/ chemical synthesis
Blood Coagulation
/ drug effects
Dose-Response Relationship, Drug
Factor XIIa
/ antagonists & inhibitors
Humans
Molecular Structure
Serine Proteinase Inhibitors
/ chemical synthesis
Structure-Activity Relationship
Thrombin
/ antagonists & inhibitors
FXIIa
aminotriazoles
covalent inhibitors
enzyme inhibitors
microscale synthesis
parallel synthesis
qNMR
thrombin
thrombosis
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
14 12 2021
14 12 2021
Historique:
received:
15
06
2021
pubmed:
20
7
2021
medline:
22
2
2022
entrez:
19
7
2021
Statut:
ppublish
Résumé
Herein we report a microscale parallel synthetic approach allowing for rapid access to libraries of N-acylated aminotriazoles and screening of their inhibitory activity against factor XIIa (FXIIa) and thrombin, which are targets for antithrombotic drugs. This approach, in combination with post-screening structure optimization, yielded a potent 7 nM inhibitor of FXIIa and a 25 nM thrombin inhibitor; both compounds showed no inhibition of the other tested serine proteases. Selected N-acylated aminotriazoles exhibited anticoagulant properties in vitro influencing the intrinsic blood coagulation pathway, but not extrinsic coagulation. Mechanistic studies of FXIIa inhibition suggested that synthesized N-acylated aminotriazoles are covalent inhibitors of FXIIa. These synthesized compounds may serve as a promising starting point for the development of novel antithrombotic drugs.
Identifiants
pubmed: 34278727
doi: 10.1002/cmdc.202100431
pmc: PMC9292294
doi:
Substances chimiques
Anticoagulants
0
Serine Proteinase Inhibitors
0
Factor XIIa
EC 3.4.21.38
Thrombin
EC 3.4.21.5
Amitrole
ZF80H5GXUF
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3672-3690Subventions
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : DVK: KA 5558/1-1
Informations de copyright
© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.
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