Abstract
Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl glutamate pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized through modifications at the 4-position of the pyridine ring and the terminal nitrogen of the piperazine ring, leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 47s with good human PRP potency, selectivity, in vivo efficacy, and oral bioavailability. Compound 47s was selected for further preclinical evaluations.
MeSH terms
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Administration, Oral
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Adolescent
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Adult
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Aged
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Animals
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Biological Availability
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CHO Cells
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Cricetinae
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Cricetulus
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Female
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Glutamates / chemical synthesis
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Glutamates / pharmacokinetics
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Humans
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Magnetic Resonance Spectroscopy
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Male
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Mass Spectrometry
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Middle Aged
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Piperazines / chemical synthesis
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Piperazines / pharmacokinetics*
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Platelet Aggregation / drug effects
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Platelet Aggregation Inhibitors / chemical synthesis
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Platelet Aggregation Inhibitors / pharmacokinetics*
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Purinergic P2 Receptor Antagonists*
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Pyridines / chemical synthesis
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Pyridines / pharmacokinetics*
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Rats
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Receptors, Purinergic P2 / metabolism
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Receptors, Purinergic P2Y12
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Structure-Activity Relationship
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Young Adult
Substances
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Glutamates
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P2RY12 protein, human
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Piperazines
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Platelet Aggregation Inhibitors
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Purinergic P2 Receptor Antagonists
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Pyridines
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Receptors, Purinergic P2
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Receptors, Purinergic P2Y12