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
Monika MarcinkowskaMarcin Kołaczkowski

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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Citations

Jul 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nikola FajkisMarcin Kolaczkowski
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Vittorio CanalePaweł Zajdel

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Methods Mentioned

BETA
column chromatography

Software Mentioned

Small
GeneSilico Metaserver
Multiplate
SwissADME
Molecule Drug Discovery Suite
LigPrep
MassLynx
Protein Preparation Wizard
QikProp
VolSurf +

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