Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro.
Pandey, Chandra Prakash
Barthwal, Manoj Kumar
Dikshit, Dinesh Kumar
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Misra, A., Prakash, P., Aggarwal, H., Dhankani, P., Kumar, S., Pandey, C. P., Pugh, N., et al. (2018). Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro.. Biochemical pharmacology, 148 288-297. https://doi.org/10.1016/j.bcp.2018.01.013
Pharmacological inhibition of platelet collagen interaction is a promising therapeutic strategy to treat intra-vascular thrombosis. S007-867 is a novel synthetic inhibitor of collagen-induced platelet aggregation. It has shown better antithrombotic protection than aspirin and clopidogrel with minimal bleeding tendency in mice. The present study is aimed to systematically investigate the antithrombotic efficacy of S007-867 in comparison to aspirin and clopidogrel in vivo and to delineate its mechanism of action in vitro. Aspirin, clopidogrel, and S007-867 significantly reduced thrombus weight in arterio-venous (AV) shunt model in rats. In mice, following ferric chloride induced thrombosis in either carotid or mesenteric artery; S007-867 significantly prolonged the vessel occlusion time (1.2 fold) and maintained a sustained blood flow velocity for >30 minutes. Comparatively, clopidogrel showed significant prolongation in TTO (1.3 fold) while aspirin remained ineffective. Both S007-867 and aspirin did not alter bleeding time in either kidney or spleen injury models, and thus maintained haemostasis, while clopidogrel showed significant increase in spleen bleeding time (1.7 fold). The coagulation parameters namely thrombin time, prothrombin time or activated partial thromboplastin time remained unaffected even at high concentration of S007-867 (300μM), thus implying its antithrombotic effect to be primarily platelet mediated. S007-867 significantly inhibited collagen-mediated platelet adhesion and aggregation in mice ex-vivo. Moreover, when blood was perfused over a highly thrombogenic combination of collagen mimicking peptides like CRP-GFOGER-VWF-III, S007-867 significantly reduced total thrombus volume or ZV50 (53.4±5.7%). Mechanistically, S007-867 (10-300μM) inhibited collagen-induced ATP release, thromboxane A2 (TxA2) generation, intra-platelet [Ca+2] flux and global tyrosine phosphorylation including PLC 2. Collectively the present study highlights that S007-867 is 4 a novel synthetic inhibitor of collagen induced platelet activation, that effectively maintains blood flow velocity and delays vascular occlusion. It inhibits thrombogenesis without compromising hemostasis. Therefore, S007-867 may be further developed for the treatment of thrombotic disorders in clinical settings.
Animals, Mice, Rats, Rats, Sprague-Dawley, Thrombosis, Chlorides, Ferric Compounds, Aspirin, Piperidines, Pyrrolidines, Fibrinolytic Agents, Platelet Adhesiveness, Blood Coagulation, Platelet Aggregation, Dose-Response Relationship, Drug, Male, Clopidogrel
Wellcome Trust (094470/Z/10/Z)
British Heart Foundation (RG/15/4/31268)
Wellcome Trust (BVS - 2010)
British Heart Foundation (RG/09/003/27122)
External DOI: https://doi.org/10.1016/j.bcp.2018.01.013
This record's URL: https://www.repository.cam.ac.uk/handle/1810/274010