Journal article Open Access

Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist

Wilkinson, Shane M; Barron, Melissa L; O'Brien-Brown, James; Janssen, Bieneke; Stokes, Leanne; Werry, Eryn L; Chishty, Mansoor; Skarratt, Kristen K; Ong, Jennifer A; Hibbs, David E; Vugts, Danielle J; Fuller, Stephen; Windhorst, Albert D; Kassiou, Michael


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    "doi": "10.1021/acschemneuro.7b00272", 
    "description": "<p><strong>Abstract</strong></p>\n\n<p>Adamantanyl benzamide <strong>1</strong> was identified as a potent P2X<sub>7</sub>R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide <strong>1</strong> to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2X<sub>7</sub>R antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability. Trifluorinated benzamide <strong>34</strong> demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide <strong>1</strong>), and an improved physicokinetic profile and proved effective in the presence of several known P2X<sub>7</sub>R polymorphisms.</p>", 
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    "title": "Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist", 
    "language": "eng", 
    "journal": {
      "volume": "8", 
      "issue": "11", 
      "pages": "2374-2380", 
      "title": "ACS Chemical Neuroscience"
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    "keywords": [
      "bioisostere", 
      "central nervous system (CNS)", 
      "metabolism", 
      "P2X7", 
      "pharmacokinetic", 
      "single nucleotide polymorphisms (SNPs)"
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    "publication_date": "2017-08-25", 
    "creators": [
      {
        "affiliation": "School of Chemistry, The University of Sydney, NSW 2006 (Australia)", 
        "name": "Wilkinson, Shane M"
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      {
        "affiliation": "Faculty of Health Sciences, The University of Sydney, NSW 2006 (Australia)", 
        "name": "Barron, Melissa L"
      }, 
      {
        "affiliation": "School of Chemistry, The University of Sydney, NSW 2006 (Australia)", 
        "name": "O'Brien-Brown, James"
      }, 
      {
        "affiliation": "Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, De Boelelaan 1117 (The Netherlands)", 
        "name": "Janssen, Bieneke"
      }, 
      {
        "affiliation": "School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ (UK)", 
        "name": "Stokes, Leanne"
      }, 
      {
        "affiliation": "Faculty of Health Sciences, The University of Sydney, NSW 2006 (Australia)", 
        "name": "Werry, Eryn L"
      }, 
      {
        "affiliation": "Pharmidex, 14 Hanover St, Mayfair, London W1S 1YH (UK)", 
        "name": "Chishty, Mansoor"
      }, 
      {
        "affiliation": "Sydney Medical School Nepean, The University of Sydney, NSW 2006 (Australia)", 
        "name": "Skarratt, Kristen K"
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      {
        "affiliation": "Faculty of Pharmacy, The University of Sydney, NSW 2006 (Australia)", 
        "name": "Ong, Jennifer A"
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      {
        "affiliation": "Faculty of Pharmacy, The University of Sydney, NSW 2006 (Australia)", 
        "name": "Hibbs, David E"
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        "affiliation": "Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, De Boelelaan 1117 (The Netherlands)", 
        "name": "Vugts, Danielle J"
      }, 
      {
        "affiliation": "Sydney Medical School Nepean, The University of Sydney, NSW 2006 (Australia)", 
        "name": "Fuller, Stephen"
      }, 
      {
        "affiliation": "Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, De Boelelaan 1117 (The Netherlands)", 
        "name": "Windhorst, Albert D"
      }, 
      {
        "affiliation": "School of Chemistry, The University of Sydney, NSW 2006 (Australia)", 
        "name": "Kassiou, Michael"
      }
    ], 
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