Part II: 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; Peter K. Harris; 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.2009.12.110

Part II: 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, Peter K. Harris, 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

14 Scopus citations

Abstract

Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog.

Original language	English
Pages (from-to)	1388-1394
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	4
DOIs	https://doi.org/10.1016/j.bmcl.2009.12.110
State	Published - Feb 15 2010

Keywords

Antiplatelet
Antithrombotic
Cardiovascular disease
GPCR antagonist
P2Y12 receptor

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10.1016/j.bmcl.2009.12.110

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Parlow, J. J., Burney, M. W., Case, B. L., Girard, T. J., Hall, K. A., Harris, P. K., Hiebsch, R. R., Huff, R. M., Lachance, R. M., Mischke, D. A., Rapp, S. R., Woerndle, R. S., & Ennis, M. D. (2010). Part II: Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y₁₂ antagonists for inhibition of platelet aggregation. Bioorganic and Medicinal Chemistry Letters, 20(4), 1388-1394. https://doi.org/10.1016/j.bmcl.2009.12.110

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

abstract = "Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog.",

keywords = "Antiplatelet, Antithrombotic, Cardiovascular disease, GPCR antagonist, P2Y12 receptor",

author = "Parlow, {John J.} and Burney, {Mary W.} and Case, {Brenda L.} and Girard, {Thomas J.} and Hall, {Kerri A.} and Harris, {Peter K.} 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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Parlow, JJ, Burney, MW, Case, BL, Girard, TJ, Hall, KA, Harris, PK, Hiebsch, RR, Huff, RM, Lachance, RM, Mischke, DA, Rapp, SR, Woerndle, RS & Ennis, MD 2010, 'Part II: Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y₁₂ antagonists for inhibition of platelet aggregation', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 4, pp. 1388-1394. https://doi.org/10.1016/j.bmcl.2009.12.110

TY - JOUR

T1 - Part II

T2 - 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 - Harris, Peter K.

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 - 2010/2/15

Y1 - 2010/2/15

N2 - Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog.

AB - Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog.

KW - Antiplatelet

KW - Antithrombotic

KW - Cardiovascular disease

KW - GPCR antagonist

KW - P2Y12 receptor

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DO - 10.1016/j.bmcl.2009.12.110

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AN - SCOPUS:75449085190

SN - 0960-894X

VL - 20

SP - 1388

EP - 1394

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 4

ER -

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

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