期刊论文详细信息
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 卷:19
Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation
Article
Parlow, John J.1  Burney, Mary W.2  Case, Brenda L.1  Girard, Thomas J.2  Hall, Kerri A.2  Hiebsch, Ronald R.2  Huff, Rita M.2  Lachance, Rhonda M.2  Mischke, Deborah A.1  Rapp, Stephen R.2  Woerndle, Rhonda S.1  Ennis, Michael D.1 
[1] Pfizer Global Res & Dev, Dept Med Chem, Chesterfield, MO 63017 USA
[2] Pfizer Global Res & Dev, Dept Biol, Chesterfield, MO 63017 USA
关键词: P2Y12 receptor;    GPCR antagonist;    Antiplatelet;    Antithrombotic;    Cardiovascular disease;    Polymer-assisted solution-phase;   
DOI  :  10.1016/j.bmcl.2009.06.075
来源: Elsevier
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【 摘 要 】

Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y(12) 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. (C) 2009 Elsevier Ltd. All rights reserved.

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