Piperazinyl glutamate pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation.

doi:10.1021/jm901518t

Paper

Piperazinyl glutamate pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation.

Published Mar 11, 2010 · J. J. Parlow, M. Burney, B. Case

Journal of medicinal chemistry

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37

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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.

Study Snapshot

Piperazinyl glutamate pyridines show potential as oral bioavailable P2Y12 antagonists for inhibiting platelet aggregation, with compound 47s showing good human platelet aggregation inhibition and oral bioavailability.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Paper

Piperazinyl glutamate pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation.

References

Citations

Pharmacological characterization of P2Y receptor subtypes – an update

Pharmacological tools can effectively characterize P2Y receptor subtypes, aiding in understanding their roles in physiology and pathophysiology.

Strategies for targeting the P2Y12 receptor in the Central Nervous System.

Targeting the P2Y12 receptor in the central nervous system could potentially lead to new treatments for degenerative diseases like multiple sclerosis and Alzheimer's disease.

Recommended tool compounds and drugs for blocking P2X and P2Y receptors

This review highlights the importance of selectively blocking P2Y and P2X receptors for studying their roles in physiology and validating them as potential drug targets.

Synthesis and biological evaluation of N 6 derivatives of 8-azapurine as novel antiplatelet agents.

N6 derivative IIh, a 4-fold better antiplatelet agent than ticagrelor, shows potential for clinical use with shorter bleeding time, less blood loss, and lower acute toxicity compared to ticagrelor.

Molecular Pharmacology of P2Y Receptor Subtypes.

P2Y receptor subtypes play a crucial role in physiology and pathophysiology, with their structural information aiding in the rational design of novel selective drugs.