Synthesis and biological evaluation of N-arylpiperazine derivatives of 4, 4-dimethylisoquinoline-1, 3(2H, 4H)-dione as potential antiplatelet agents. (1st January 2018)

• Record Type: Journal Article
• Authors: Marcinkowska, Monika; Kotańska, Magdalena; Zagórska, Agnieszka; Śniecikowska, Joanna; Kubacka, Monika; Siwek, Agata; Bucki, Adam; Pawłowski, Maciej; Bednarski, Marek; Sapa, Jacek; Starek, Małgorzata; Dąbrowska, Monika; Kołaczkowski, Marcin
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 33:Number 1(2018)
• Page Start: 536
• Page End: 545
• Publication Date: 2018-01-01
• Subjects: Antiplatelet agents -- blockade of the platelet aggregation -- alpha 2B receptor antagonists -- ARC-239; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2018.1437155
• Languages: English
• ISSNs: 1475-6366

Abstract

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(2 H, 4 H )-dione as potential alpha 2B receptor antagonists. The most potent compound3, 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. Graphical Abstract: