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

This study presents a novel series of <i>N</i>-acylated 1,2,4-triazol-5-amines and 1<i>H</i>-pyrazol-5-amines, featuring a pyrazin-2-yl moiety, developed as covalent inhibitors of thrombin. These compounds demonstrated potent inhibitory activity, with derivatives <b>13a</b> and <b>13b</b> achieving IC<sub>50</sub> 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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Publication Details

Journal
ACS Pharmacology & Translational Science
Published
2024-12-11
DOI
https://doi.org/10.1021/acsptsci.4c00515
Citations
2
Primary Topic
Click Chemistry and Applications
Type
article
Field-Weighted Citation Impact
0.50

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article

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

Katrin Nekipelov, Marcel Bermúdez, Thanigaimalai Pillaiyar, Ruzanna A. Ovsepyan et al.
2 citations
ACS Pharmacology & Translational Science
Click Chemistry and Applications
0.50
article

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

Katrin Nekipelov, Marcel Bermúdez, Thanigaimalai Pillaiyar, Ruzanna A. Ovsepyan, Catharina Erbacher, Svetlana A. Kalinina, Judith Schmidt, Dmitrii V. Kalinin, Gerd Bendas, Constantin G. Daniliuc, Anthony J. O’Donoghue, Mikhail A. Panteleev, Uwe Kärst, Ellen Gonçalves de Oliveira, Alena I. Siutkina, Lukas Imberg, Antti Poso, Mateus Sá Magalhães Serafim, Darius F. Broekmans
article en
2 citations

Abstract

This study presents a novel series of <i>N</i>-acylated 1,2,4-triazol-5-amines and 1<i>H</i>-pyrazol-5-amines, featuring a pyrazin-2-yl moiety, developed as covalent inhibitors of thrombin. These compounds demonstrated potent inhibitory activity, with derivatives <b>13a</b> and <b>13b</b> achieving IC<sub>50</sub> 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.

ACS Pharmacology & Translational ScienceVol. 8(1)
Universidade Federal de Minas Gerais (BR), University of Bonn (DE), University of Eastern Finland (FI), University of Münster (DE), Center for Theoretical Problems of Physicochemical Pharmacology (RU), University Children's Hospital Tübingen (DE), Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology (RU), Bernstein Center for Computational Neuroscience Tübingen (DE), Center for Discovery (US), University of Montana (US), University of Tübingen (DE)
Itä-Suomen Yliopisto, Deutsche Forschungsgemeinschaft, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Universidade Federal de Minas Gerais, Rheinische Friedrich-Wilhelms-Universität Bonn, Directorate for Biological Sciences, University of California, San Diego, Russian Academy of Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences
Openalex Percentile: Top 37%
Click Chemistry and Applications
0.50
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