Multitarget Antithrombotic Drugs

Abstract

Thromboembolic disorders are still the leading causes of morbidity and mortality in developed societies. Therefore, prophylaxis and treatment of arterial and venous thrombosis are among the main therapeutic challenges nowadays. Simultaneous action on several targets involved in pathology of thrombosis offers potential advantages compared to existing drugs which were developed as selective modulators of single targets. The review focuses on dual inhibitors of coagulation enzymes, dual antiaggregatory compounds exerting their action on different combinations of platelet targets, as well as on anticoagulant/antiaggregatory compounds which interfere with at least one target involved in blood coagulation and at least one target engaged in the process leading to platelet aggregation.

Dual Inhibitors of Human DNA Topoisomerase II and Other Cancer-Related Targets

“…Multitarget therapies have for many years attracted the interest of medicinal chemists in the field of complex diseases, such as cancers, inflammation, psychiatric disorders, and thrombotic disorders. − These diseases can be affected by many factors, and they are often resilient to single-target treatments due to activation of compensatory mechanisms and redundant cellular pathways . Despite the many challenges of cancer therapies, current chemotherapeutics and targeted drugs can significantly prolong patient lives and in some cases also cure the disease .…”

Discovery of phenylsulfonylfuroxan derivatives as gamma globin inducers by histone acetylation

“…In addition, tissue injury and platelet activation produce a state of hypercoagulability in SCD patients [39]. In humans, antagonists of the P2Y 12 adenosine diphosphate (ADP) receptor have shown the capacity to reduce the hypercoagulability state in SCD, preventing the vaso-occlusion process [6,54]. Prasugrel, for example, decreased platelet adherence to monocytes and neutrophils, reducing the cell-platelet aggregate size [55].…”

“…Infrared (IR) spectroscopy (KBr disc) were performed on an FTIR-8300 Shimadzu spectrometer, and the frequencies are expressed per cm À1 . The nuclear magnetic resonance (NMR) for 1 H and 13 C of all compounds were scanned on a Bruker Fourier with Dual probe 13 Compounds 1, 6(a-b) and 9 were synthesized according to a previously described methodologies [18,54,59].…”

Synthesis and Evaluation of Spumigin Analogues Library with Thrombin Inhibitory Activity

“…Docking of the spumigin J to thrombin demonstrated that the amino group of methyllysine binds to the S1 pocket of the thrombin active site, while the (2 S ,4 S )-4-methylproline ring was bound in the hydrophobic pocket S2 and homotyrosine established the hydrophobic interactions with a hydrophobic aryl-S3 binding site [ 5 ]. Therefore, spumigins with (2 S ,4 S )-4-methylproline central core represent interesting starting compounds for the development of a new structural type of direct thrombin inhibitors [ 9 , 10 , 11 , 12 ]. Herein, we report a series of new types of direct thrombin inhibitors based on the tetrapeptide structure of spumigins, where the (2 S ,4 S )-4-methylproline central core was replaced in first series with an indoline ring as a more hydrophobic and rigid core, and in the second series of analogues with a more flexible l -proline core.…”