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.\}",

year = "2009",

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

language = "English",

volume = "19",

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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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T1 - Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation

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

UR - https://www.scopus.com/pages/publications/67651087350

U2 - 10.1016/j.bmcl.2009.06.075

DO - 10.1016/j.bmcl.2009.06.075

M3 - Article

C2 - 19604694

AN - SCOPUS:67651087350

SN - 0960-894X

VL - 19

SP - 4657

EP - 4663

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 16

ER -

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

Abstract

Keywords

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