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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", 
  "container_title": "ACS Chemical Neuroscience", 
  "language": "eng", 
  "title": "Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist", 
  "issued": {
    "date-parts": [
      [
        2017, 
        8, 
        25
      ]
    ]
  }, 
  "abstract": "<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>", 
  "author": [
    {
      "family": "Wilkinson, Shane M"
    }, 
    {
      "family": "Barron, Melissa L"
    }, 
    {
      "family": "O'Brien-Brown, James"
    }, 
    {
      "family": "Janssen, Bieneke"
    }, 
    {
      "family": "Stokes, Leanne"
    }, 
    {
      "family": "Werry, Eryn L"
    }, 
    {
      "family": "Chishty, Mansoor"
    }, 
    {
      "family": "Skarratt, Kristen K"
    }, 
    {
      "family": "Ong, Jennifer A"
    }, 
    {
      "family": "Hibbs, David E"
    }, 
    {
      "family": "Vugts, Danielle J"
    }, 
    {
      "family": "Fuller, Stephen"
    }, 
    {
      "family": "Windhorst, Albert D"
    }, 
    {
      "family": "Kassiou, Michael"
    }
  ], 
  "page": "2374-2380", 
  "volume": "8", 
  "type": "article-journal", 
  "issue": "11", 
  "id": "1048167"
}
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