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 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 22J with good human PRP potency, selectivity, in vivo efficacy and oral bioavailability.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Glutamic Acid / chemistry*
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Humans
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Male
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Piperazines / chemistry*
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Platelet Aggregation / drug effects*
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Platelet Aggregation Inhibitors / chemistry*
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Platelet Aggregation Inhibitors / pharmacokinetics
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Platelet Aggregation Inhibitors / pharmacology
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Purinergic P2 Receptor Antagonists*
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Pyridines / chemistry*
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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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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
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 P2 Receptor Antagonists
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Pyridines
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Receptors, Purinergic P2
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Receptors, Purinergic P2Y12
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Recombinant Proteins
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Glutamic Acid