2. Academic Validation
  3. Amide-functionalized 1,2,4-Triazol-5-amines as Covalent Inhibitors of Blood Coagulation Factor XIIa and Thrombin

Amide-functionalized 1,2,4-Triazol-5-amines as Covalent Inhibitors of Blood Coagulation Factor XIIa and Thrombin

  • ACS Pharmacol Transl Sci. 2022 Nov 30;5(12):1318-1347. doi: 10.1021/acsptsci.2c00204.
Lukas Imberg 1,  Simon Platte 1,  Catharina Erbacher 2,  Constantin G Daniliuc 3,  Svetlana A Kalinina 4,  Wolfgang Dörner 5,  Antti Poso 6 7,  Uwe Karst 2,  Dmitrii V Kalinin 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster 48149, Germany.
  • 2 Institute of Inorganic and Analytical Chemistry, University of Münster, Münster 48149, Germany.
  • 3 Institute for Organic Chemistry, University of Münster, Münster 48149, Germany.
  • 4 Institute of Food Chemistry, University of Münster, Münster 48149, Germany.
  • 5 Institute of Biochemistry, University of Münster, Münster 48149, Germany.
  • 6 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio 70211, Finland.
  • 7 Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen 72076, Germany.
PMID: 36524012 DOI: 10.1021/acsptsci.2c00204
Abstract

To counteract thrombosis, new safe and efficient antithrombotics are required. We herein report the design, synthesis, and biological activity of a series of amide-functionalized acylated 1,2,4-triazol-5-amines as selective inhibitors of blood coagulation factor XIIa and Thrombin. The introduction of an amide moiety into the main scaffold of 3-aryl aminotriazoles added certain three-dimensional properties to synthesized compounds and allowed them to reach binding sites in FXIIa and Thrombin previously unaddressed by non-functionalized 1,2,4-triazol-5-amines. Among synthesized compounds, one quinoxaline-derived aminotriazole bearing N-butylamide moiety inhibited FXIIa with the IC50 value of 28 nM, whereas the N-phenylamide-derived aminotriazole inhibited Thrombin with the IC50 value of 41 nM. Performed mass-shift experiments and molecular modeling studies proved the covalent mechanism of FXIIa and Thrombin inhibition by synthesized compounds. In plasma coagulation tests, developed aminotriazoles showed anticoagulant properties mainly affecting the intrinsic blood coagulation pathway, activation of which is associated with thrombosis but is negligible for hemostasis.

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