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

John J. Parlow; Mary W. Burney; Brenda L. Case; Thomas J. Girard; Kerri A. Hall; Ronald R. Hiebsch; Rita M. Huff; Rhonda M. Lachance; Deborah A. Mischke; Stephen R. Rapp; Rhonda S. Woerndle; Michael D. Ennis

doi:10.1016/j.bmcl.2009.06.075

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

John J. Parlow, Mary W. Burney, Brenda L. Case, Thomas J. Girard, Kerri A. Hall, Ronald R. Hiebsch, Rita M. Huff, Rhonda M. Lachance, Deborah A. Mischke, Stephen R. Rapp, Rhonda S. Woerndle, Michael D. Ennis

Department of Pediatrics

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y₁₂ 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.

Original language	English
Pages (from-to)	4657-4663
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2009.06.075
State	Published - Aug 15 2009

Keywords

Antiplatelet
Antithrombotic
Cardiovascular disease
GPCR antagonist
P2Y12 receptor
Polymer-assisted solution-phase

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10.1016/j.bmcl.2009.06.075

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Parlow, J. J., Burney, M. W., Case, B. L., Girard, T. J., Hall, K. A., Hiebsch, R. R., Huff, R. M., Lachance, R. M., Mischke, D. A., Rapp, S. R., Woerndle, R. S., & Ennis, M. D. (2009). Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y₁₂ antagonists for inhibition of platelet aggregation. Bioorganic and Medicinal Chemistry Letters, 19(16), 4657-4663. https://doi.org/10.1016/j.bmcl.2009.06.075

@article{814c4050e5074198b4cbee92c4bac757,

title = "Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation",

abstract = "Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y12 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.",

keywords = "Antiplatelet, Antithrombotic, Cardiovascular disease, GPCR antagonist, P2Y12 receptor, Polymer-assisted solution-phase",

author = "Parlow, {John J.} and Burney, {Mary W.} and Case, {Brenda L.} and Girard, {Thomas J.} and Hall, {Kerri A.} and Hiebsch, {Ronald R.} and Huff, {Rita M.} and Lachance, {Rhonda M.} and Mischke, {Deborah A.} and Rapp, {Stephen R.} and Woerndle, {Rhonda S.} and Ennis, {Michael D.}",

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doi = "10.1016/j.bmcl.2009.06.075",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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Parlow, JJ, Burney, MW, Case, BL, Girard, TJ, Hall, KA, Hiebsch, RR, Huff, RM, Lachance, RM, Mischke, DA, Rapp, SR, Woerndle, RS & Ennis, MD 2009, 'Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y₁₂ antagonists for inhibition of platelet aggregation', Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 16, pp. 4657-4663. https://doi.org/10.1016/j.bmcl.2009.06.075

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AU - Parlow, John J.

AU - Burney, Mary W.

AU - Case, Brenda L.

AU - Girard, Thomas J.

AU - Hall, Kerri A.

AU - Hiebsch, Ronald R.

AU - Huff, Rita M.

AU - Lachance, Rhonda M.

AU - Mischke, Deborah A.

AU - Rapp, Stephen R.

AU - Woerndle, Rhonda S.

AU - Ennis, Michael D.

PY - 2009/8/15

Y1 - 2009/8/15

N2 - Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y12 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.

AB - Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y12 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.

KW - Antiplatelet

KW - Antithrombotic

KW - Cardiovascular disease

KW - GPCR antagonist

KW - P2Y12 receptor

KW - Polymer-assisted solution-phase

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IS - 16

ER -

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

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Keywords

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