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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day = "15",

doi = "10.1016/j.bmcl.2009.12.110",

language = "English",

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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

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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

UR - https://www.scopus.com/pages/publications/75449085190

U2 - 10.1016/j.bmcl.2009.12.110

DO - 10.1016/j.bmcl.2009.12.110

M3 - Article

C2 - 20097563

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

Abstract

Keywords

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