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

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21 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 languageEnglish
Pages (from-to)4657-4663
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number16
DOIs
StatePublished - Aug 15 2009

Keywords

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

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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