Monika Marcinkowska1, Magdalena Kotańska2, Agnieszka Zagórska1, Joanna Śniecikowska1, Monika Kubacka2, Agata Siwek3, Adam Bucki1, Maciej Pawłowski1, Marek Bednarski4, Jacek Sapa4, Małgorzata Starek5, Monika Dąbrowska5, Marcin Kołaczkowski1. 1. a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland. 2. b Department of Pharmacological Screening , Chair of Pharmacodynamics, Jagiellonian University Medical College , Krakó , Poland. 3. c Department of Pharmacobiology , Jagiellonian University Medical College , Kraków , Poland. 4. d Department of Pharmacological Screening , Chair of Pharmacodynamics, Jagiellonian University Medical College , Kraków , Poland. 5. e Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy , Jagiellonian University Medical College , Krakow , Poland.
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.
Despite the substantial clinical success of aspirin and n class="Chemical">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.
Entities:
Keywords:
ARC-239; Antiplatelet agents; alpha 2B receptor antagonists; blockade of the platelet aggregation
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