Synthesis and Biological Evaluation of Direct Thrombin Inhibitors Bearing 4-(Piperidin-1-yl)pyridine at the P1 Position with Potent Anticoagulant Activity

2013 ◽  
Vol 56 (21) ◽  
pp. 8696-8711 ◽  
Author(s):  
Modesto de Candia ◽  
Filomena Fiorella ◽  
Gianfranco Lopopolo ◽  
Andrea Carotti ◽  
Maria Rosaria Romano ◽  
...  
Keyword(s):  
Anticoagulant Activity ◽  
Biological Evaluation ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Synthesis And Biological Evaluation

scholarly journals Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cho Yeow Koh ◽  
Norrapat Shih ◽  
Christina Y. C. Yip ◽  
Aaron Wei Liang Li ◽  
Weiming Chen ◽  
...  
Keyword(s):  
Antiplatelet Therapy ◽  
Anticoagulant Activity ◽  
Standard Of Care ◽  
Therapeutic Index ◽  
Coronary Intervention ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Human Antibody ◽  
Next Generation ◽  
Pharmacologic Activity

AbstractDespite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.

scholarly journals Synthesis and Evaluation of Spumigin Analogues Library with Thrombin Inhibitory Activity

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 413 ◽  
Author(s):  
Aleš Žula ◽  
Izabela Będziak ◽  
Danijel Kikelj ◽  
Janez Ilaš
Keyword(s):  
Inhibitory Activity ◽  
Serine Proteases ◽  
Biological Effects ◽  
Factor Xa ◽  
Structural Type ◽  
Biological Evaluation ◽  
Central Core ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Lead Compounds

Spumigins are marine natural products derived from cyanobacteria Nodularia spumigena, which mimics the structure of the d-Phe-Pro-Arg sequence and is crucial for binding to the active site of serine proteases thrombin and factor Xa. Biological evaluation of spumigins showed that spumigins with a (2S,4S)-4-methylproline central core represent potential lead compounds for the development of a new structural type of direct thrombin inhibitors. Herein, we represent synthesis and thrombin inhibitory activity of a focused library of spumigins analogues with indoline ring or l-proline as a central core. Novel compounds show additional insight into the structure and biological effects of spumigins. The most active analogue was found to be a derivative containing l-proline central core with low micromolar thrombin inhibitory activity.

Statistical Molecular Design, Parallel Synthesis, and Biological Evaluation of a Library of Thrombin Inhibitors

2001 ◽  
Vol 44 (21) ◽  
pp. 3424-3439 ◽  
Author(s):  
Anna Linusson ◽  
Johan Gottfries ◽  
Thomas Olsson ◽  
Eivor Örnskov ◽  
Staffan Folestad ◽  
...  
Keyword(s):  
Molecular Design ◽  
Biological Evaluation ◽  
Parallel Synthesis ◽  
Thrombin Inhibitors ◽  
Synthesis And Biological Evaluation ◽  
Statistical Molecular Design

Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold

2007 ◽  
Vol 5 (16) ◽  
pp. 2599 ◽  
Author(s):  
David Blomberg ◽  
Tomas Fex ◽  
Yafeng Xue ◽  
Kay Brickmann ◽  
Jan Kihlberg
Keyword(s):  
Biological Evaluation ◽  
Thrombin Inhibitors ◽  
Design Synthesis ◽  
Synthesis And Biological Evaluation

Design, Synthesis, and Biological Evaluation of Dabigatran Etexilate Mimics, a Novel Class of Thrombin Inhibitors

2015 ◽  
Vol 348 (8) ◽  
pp. 595-605 ◽  
Author(s):  
Shaochi Wang ◽  
Peng Dai ◽  
Yungen Xu ◽  
Qiufang Chen ◽  
Qihua Zhu ◽  
...  
Keyword(s):  
Dabigatran Etexilate ◽  
Biological Evaluation ◽  
Thrombin Inhibitors ◽  
Design Synthesis ◽  
Synthesis And Biological Evaluation

Design, synthesis and biological evaluation of selective boron-containing thrombin inhibitors

1999 ◽  
Vol 7 (7) ◽  
pp. 1295-1307 ◽  
Author(s):  
Anette Wienand ◽  
Claus Ehrhardt ◽  
Rainer Metternich ◽  
Carlo Tapparelli
Keyword(s):  
Biological Evaluation ◽  
Thrombin Inhibitors ◽  
Design Synthesis ◽  
Synthesis And Biological Evaluation
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