Abstract
A series of novel, highly potent P2Y₁₂ antagonists as inhibitors of platelet aggregation based on a phenylpyrazole glutamic acid piperazine backbone is described. Exploration of the structural requirements of the substituents by probing the structure-activity relationship along this backbone led to the discovery of the N-acetyl-(S)-proline cyclobutyl amide moiety as a highly privileged motif. Combining the most favorable substituents led to remarkably potent P2Y₁₂ antagonists displaying not only low nanomolar binding affinity to the P2Y₁₂ receptor but also a low nanomolar inhibition of platelet aggregation in the human platelet rich plasma assay with IC₅₀ values below 50 nM. Using a homology and a three-dimensional quantitative structure-activity relationship model, a binding hypothesis elucidating the impact of several structural features was developed.
MeSH terms
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Animals
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CHO Cells
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Cricetinae
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Cricetulus
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Glutamic Acid / analogs & derivatives*
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Glutamic Acid / chemical synthesis*
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Glutamic Acid / chemistry
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Glutamic Acid / pharmacology
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Humans
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Molecular Docking Simulation
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Platelet Aggregation / drug effects
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Platelet Aggregation Inhibitors / chemical synthesis
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Platelet Aggregation Inhibitors / chemistry
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Platelet Aggregation Inhibitors / pharmacology
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Purinergic P2Y Receptor Antagonists / chemical synthesis*
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Purinergic P2Y Receptor Antagonists / chemistry
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Purinergic P2Y Receptor Antagonists / pharmacology
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Quantitative Structure-Activity Relationship
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Radioligand Assay
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Receptors, Purinergic P2Y12 / metabolism*
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Stereoisomerism
Substances
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P2RY12 protein, human
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Piperazines
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Platelet Aggregation Inhibitors
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Purinergic P2Y Receptor Antagonists
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Pyrazoles
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Receptors, Purinergic P2Y12
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Glutamic Acid