Barker, D

Binsaleh, N

Daniels, S

Dempsey-Hibbert, N

Jones, S

Moreno-Martinez, D

Pilkington, L

van Rensburg, M

Whitehead, K

Wigley, C

E-space: Manchester Metropolitan University's Research Repository

NOVEL THIENOPYRIDINES AS POTENT PLATELET INHIBITORS: FUTURE TREATMENTS FOR PLATELET HYPERACTIVITY DISORDERS?  Naif Binsaleh* 1, Catherine Wigley1, Kathryn Whitehead1, Daniel Moreno-Martinez1, Sarah Daniels1, Sarah Jones1, Michelle van Rensburg2, Lisa Pilkington2, David Barker2, Nina Dempsey-Hibbert1 1School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom, 2School of Chemical Sciences, University of Auckland, Auckland, New Zealand   Background: Platelet hyperactivity is associated with a number of disorders including Acute Coronary Syndromes (ACS) and manifests as increased platelet activation and often inappropriate thrombus formation. The thienopyridine class of anti-platelet drugs, of which clopidogrel and prasurgrel are the most well-known, target the P2Y12 receptor on platelets, blocking the effects of the platelet agonist ADP. However, the effect of these drugs is variable amongst patients, with some patients responding well and some remaining at risk of thrombosis. This variability highlights a need for a refinement of this class of P2Y12 inhibitor.  Aims: The aim of this study was to assess the efficacy of six novel thienopyridine derivatives synthesized by our group by examining their potential as in-vitro inhibitors of platelet function. Methods: Healthy human platelets were isolated and incubated with novel thienopyridine compounds (DJ0081, DJ0199, DJ0021,DJ0206, DJ0171, DJ0097) (10μM, 30min) prior to stimulation with ADP (10μM) and analysis of alpha granule secretion (CD62P expression), GPIIbIIIa activation (PAC1 expression) and platelet leukocyte aggregate (PLA) formation using flow cytometry. Furthermore, light transmission aggregometry (LTA) was used to assess ADP-stimulated aggregation after these treatments. As clopidogrel is usually prescribed in combination with the COX-1 inhibitor acetylsalicylic acid (ASA), synergy of the novel compounds with ASA (30μM) was also analysed by LTA. All results were compared to ADP-stimulated samples and samples treated with clopidogrel (10μM, 30min) prior to ADP stimulation.  Results: All six novel compounds demonstrated a significant reduction in ADP-mediated platelet aggregation (P<0.001), CD62P expression (p<0.001), PAC1 expression (p<0.01) and PLA formation (p<0.05). These compounds were also shown to enhance the inhibitory effects of ASA. DJ0171 and DJ0199 were particularly potent, displaying greater inhibitory effect than clopidogrel.  Summary/Conclusion: The study demonstrates the potential for new thienopyridine compounds as modulators of platelet function and points to the possibility of future use in patients at risk of platelet hyperactivity and thrombosis.  Keywords: Inhibitor, Platelet activation, Platelet aggregation, Thrombosis 

Novel thienopyridines as potent platelet inhibitors: future treatments for platelet hyperactivity disorders?

https://e-space.mmu.ac.uk/621631/1/NOVEL%20THIENOPYRIDINES%20AS%20POTENT%20PLATELET%20INHIBITORS.pdf

Novel thienopyridines as potent platelet inhibitors: future treatments for platelet hyperactivity disorders?

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