Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents

Journal of Enzyme Inhibition and Medicinal Chemistry

Małgorzata Starek¹  Monika Dąbrowska¹  Monika Marcinkowska²  Marcin Kołaczkowski²  Adam Bucki²  Joanna Śniecikowska²  Agnieszka Zagórska²  Maciej Pawłowski²  Agata Siwek³  Monika Kubacka⁴  Magdalena Kotańska⁴  Marek Bednarski⁵  Jacek Sapa⁵ 

[1] Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Polan;Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland;Department of Pharmacobiology, Jagiellonian University Medical College, Kraków, Poland;Department of Pharmacological Screening, Chair of Pharmacodynamics, Jagiellonian University Medical College, Krakó, Poland;Department of Pharmacological Screening, Chair of Pharmacodynamics, Jagiellonian University Medical College, Kraków, Poland;

关键词: Antiplatelet agents;    blockade of the platelet aggregation;    alpha 2B receptor antagonists;    ARC-239;   

DOI  :  10.1080/14756366.2018.1437155

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY