Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents |
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Authors: | Monika Marcinkowska Magdalena Kotańska Agnieszka Zagórska Joanna Śniecikowska Monika Kubacka Agata Siwek |
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Affiliation: | 1. Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland;2. Department of Pharmacological Screening, Chair of Pharmacodynamics, Jagiellonian University Medical College, Krakó, Poland;3. Department of Pharmacobiology, Jagiellonian University Medical College, Kraków, Poland |
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Abstract: | Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC50 of 26.9?μM and 20.5?μM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action. |
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Keywords: | Antiplatelet agents blockade of the platelet aggregation alpha 2B receptor antagonists ARC-239 |
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