2. Academic Validation
  3. Pyrazinyl-Substituted Aminoazoles as Covalent Inhibitors of Thrombin: Synthesis, Structure, and Anticoagulant Properties

Pyrazinyl-Substituted Aminoazoles as Covalent Inhibitors of Thrombin: Synthesis, Structure, and Anticoagulant Properties

  • ACS Pharmacol Transl Sci. 2024 Dec 11;8(1):146-172. doi: 10.1021/acsptsci.4c00515.
Lukas Imberg 1,  Alena I Siutkina 1,  Catharina Erbacher 2,  Judith Schmidt 1,  Darius F Broekmans 1,  Ruzanna A Ovsepyan 3,  Constantin G Daniliuc 4,  Ellen Gonçalves de Oliveira 5 6,  Mateus Sá Magalhães Serafim 5 6,  Anthony J O'Donoghue 5,  Thanigaimalai Pillaiyar 7 8,  Mikhail A Panteleev 3 9,  Antti Poso 10 11,  Svetlana A Kalinina 12,  Marcel Bermúdez 1,  Katrin Nekipelov 13,  Gerd Bendas 13,  Uwe Karst 2,  Dmitrii V Kalinin 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, 48149 Münster, Germany.
  • 2 Institute of Inorganic and Analytical Chemistry, University of Münster, 48149 Münster, Germany.
  • 3 Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, 119991 Moscow, Russia.
  • 4 Institute for Organic Chemistry, University of Münster, 48149 Münster, Germany.
  • 5 Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, San Diego, California 92093, United States.
  • 6 Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, 31270-901 Belo Horizonte, Minas Gerais, Brazil.
  • 7 Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
  • 8 Tübingen Center for Academic Drug Discovery (TüCAD2), 72076 Tübingen, Germany.
  • 9 Laboratory of Translational Medicine, Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, 117997 Moscow, Russia.
  • 10 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • 11 Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany.
  • 12 Institute of Food Chemistry, University of Münster, Münster 48149, Germany.
  • 13 Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany.
PMID: 39816788 DOI: 10.1021/acsptsci.4c00515
Abstract

This study presents a novel series of N-acylated 1,2,4-triazol-5-amines and 1H-pyrazol-5-amines, featuring a pyrazin-2-yl moiety, developed as covalent inhibitors of Thrombin. These compounds demonstrated potent inhibitory activity, with derivatives 13a and 13b achieving IC50 values as low as 0.7 and 0.8 nM, respectively. Mass-shift assays confirmed that these inhibitors covalently bind to the catalytic Ser195 of Thrombin, leading to temporary inhibition of its activity through specific acylation. The anticoagulant efficacy of these compounds was validated in plasma coagulation assays, with selected derivatives extending coagulation times in both an activated partial thromboplastin time (aPTT) and prothrombin time (PT) test. Thrombin generation assays further demonstrated that compounds of this series effectively reduced Thrombin generation without substantially prolonging clotting times, suggesting a lower risk of bleeding. Selected compounds also strongly inhibited Cancer cell- and thrombin-induced platelet aggregation. These results indicate that acylated aminoazoles hold a promise as new anticoagulants.

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