Abstract
Piperazinyl-glutamate-pyrimidines were prepared with oxygen, nitrogen, and sulfur substitution at the 4-position of the pyrimidine leading to highly potent P2Y12 antagonists. In particular, 4-substituted piperidine-4-pyrimidines provided compounds with exceptional potency. Pharmacokinetic and physicochemical properties were fine-tuned through modifications at the 4-position of the piperidine ring leading to compounds with good human PRP potency, selectivity, clearance and oral bioavailability.
MeSH terms
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Animals
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Fibrinolytic Agents / chemical synthesis
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Fibrinolytic Agents / chemistry*
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Fibrinolytic Agents / pharmacokinetics
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Glutamic Acid / chemistry*
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Humans
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Male
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Piperidines / chemistry*
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Platelet Aggregation / drug effects*
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Purinergic P2 Receptor Antagonists*
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Receptors, Purinergic P2 / metabolism
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Receptors, Purinergic P2Y12
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Structure-Activity Relationship
Substances
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Fibrinolytic Agents
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P2RY12 protein, human
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Piperidines
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Purinergic P2 Receptor Antagonists
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Pyrimidines
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Receptors, Purinergic P2
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Receptors, Purinergic P2Y12
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Glutamic Acid
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piperidine