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Microscale Parallel Synthesis of Acylated Aminotriazoles Enabling the Development of Factor XIIa and Thrombin Inhibitors
Author(s) -
Platte Simon,
Korff Marvin,
Imberg Lukas,
Balicioglu Ilker,
Erbacher Catharina,
Will Jonas M.,
Daniliuc Constantin G.,
Karst Uwe,
Kalinin Dmitrii V.
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100431
Subject(s) - thrombin , antithrombotic , chemistry , proteases , discovery and development of direct thrombin inhibitors , coagulation , kallikrein , serine , biochemistry , pharmacology , combinatorial chemistry , enzyme , biology , medicine , immunology , platelet , psychiatry , cardiology
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.