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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  <identifier identifierType="URL">https://zenodo.org/record/1048167</identifier>
  <creators>
    <creator>
      <creatorName>Wilkinson, Shane M</creatorName>
      <givenName>Shane M</givenName>
      <familyName>Wilkinson</familyName>
      <affiliation>School of Chemistry, The University of Sydney, NSW 2006 (Australia)</affiliation>
    </creator>
    <creator>
      <creatorName>Barron, Melissa L</creatorName>
      <givenName>Melissa L</givenName>
      <familyName>Barron</familyName>
      <affiliation>Faculty of Health Sciences, The University of Sydney, NSW 2006 (Australia)</affiliation>
    </creator>
    <creator>
      <creatorName>O'Brien-Brown, James</creatorName>
      <givenName>James</givenName>
      <familyName>O'Brien-Brown</familyName>
      <affiliation>School of Chemistry, The University of Sydney, NSW 2006 (Australia)</affiliation>
    </creator>
    <creator>
      <creatorName>Janssen, Bieneke</creatorName>
      <givenName>Bieneke</givenName>
      <familyName>Janssen</familyName>
      <affiliation>Department of Radiology &amp; Nuclear Medicine, VU University Medical Center, Amsterdam, De Boelelaan 1117 (The Netherlands)</affiliation>
    </creator>
    <creator>
      <creatorName>Stokes, Leanne</creatorName>
      <givenName>Leanne</givenName>
      <familyName>Stokes</familyName>
      <affiliation>School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ (UK)</affiliation>
    </creator>
    <creator>
      <creatorName>Werry, Eryn L</creatorName>
      <givenName>Eryn L</givenName>
      <familyName>Werry</familyName>
      <affiliation>Faculty of Health Sciences, The University of Sydney, NSW 2006 (Australia)</affiliation>
    </creator>
    <creator>
      <creatorName>Chishty, Mansoor</creatorName>
      <givenName>Mansoor</givenName>
      <familyName>Chishty</familyName>
      <affiliation>Pharmidex, 14 Hanover St, Mayfair, London W1S 1YH (UK)</affiliation>
    </creator>
    <creator>
      <creatorName>Skarratt, Kristen K</creatorName>
      <givenName>Kristen K</givenName>
      <familyName>Skarratt</familyName>
      <affiliation>Sydney Medical School Nepean, The University of Sydney, NSW 2006 (Australia)</affiliation>
    </creator>
    <creator>
      <creatorName>Ong, Jennifer A</creatorName>
      <givenName>Jennifer A</givenName>
      <familyName>Ong</familyName>
      <affiliation>Faculty of Pharmacy, The University of Sydney, NSW 2006 (Australia)</affiliation>
    </creator>
    <creator>
      <creatorName>Hibbs, David E</creatorName>
      <givenName>David E</givenName>
      <familyName>Hibbs</familyName>
      <affiliation>Faculty of Pharmacy, The University of Sydney, NSW 2006 (Australia)</affiliation>
    </creator>
    <creator>
      <creatorName>Vugts, Danielle J</creatorName>
      <givenName>Danielle J</givenName>
      <familyName>Vugts</familyName>
      <affiliation>Department of Radiology &amp; Nuclear Medicine, VU University Medical Center, Amsterdam, De Boelelaan 1117 (The Netherlands)</affiliation>
    </creator>
    <creator>
      <creatorName>Fuller, Stephen</creatorName>
      <givenName>Stephen</givenName>
      <familyName>Fuller</familyName>
      <affiliation>Sydney Medical School Nepean, The University of Sydney, NSW 2006 (Australia)</affiliation>
    </creator>
    <creator>
      <creatorName>Windhorst, Albert D</creatorName>
      <givenName>Albert D</givenName>
      <familyName>Windhorst</familyName>
      <affiliation>Department of Radiology &amp; Nuclear Medicine, VU University Medical Center, Amsterdam, De Boelelaan 1117 (The Netherlands)</affiliation>
    </creator>
    <creator>
      <creatorName>Kassiou, Michael</creatorName>
      <givenName>Michael</givenName>
      <familyName>Kassiou</familyName>
      <affiliation>School of Chemistry, The University of Sydney, NSW 2006 (Australia)</affiliation>
    </creator>
  </creators>
  <titles>
    <title>Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist</title>
  </titles>
  <publisher>Zenodo</publisher>
  <publicationYear>2017</publicationYear>
  <subjects>
    <subject>bioisostere</subject>
    <subject>central nervous system (CNS)</subject>
    <subject>metabolism</subject>
    <subject>P2X7</subject>
    <subject>pharmacokinetic</subject>
    <subject>single nucleotide polymorphisms (SNPs)</subject>
  </subjects>
  <dates>
    <date dateType="Issued">2017-08-25</date>
  </dates>
  <language>en</language>
  <resourceType resourceTypeGeneral="Text">Journal article</resourceType>
  <alternateIdentifiers>
    <alternateIdentifier alternateIdentifierType="url">https://zenodo.org/record/1048167</alternateIdentifier>
  </alternateIdentifiers>
  <relatedIdentifiers>
    <relatedIdentifier relatedIdentifierType="DOI" relationType="IsIdenticalTo">10.1021/acschemneuro.7b00272</relatedIdentifier>
    <relatedIdentifier relatedIdentifierType="URL" relationType="IsPartOf">https://zenodo.org/communities/inmind</relatedIdentifier>
  </relatedIdentifiers>
  <rightsList>
    <rights rightsURI="http://creativecommons.org/licenses/by/4.0/legalcode">Creative Commons Attribution 4.0 International</rights>
    <rights rightsURI="info:eu-repo/semantics/openAccess">Open Access</rights>
  </rightsList>
  <descriptions>
    <description descriptionType="Abstract">&lt;p&gt;&lt;strong&gt;Abstract&lt;/strong&gt;&lt;/p&gt;

&lt;p&gt;Adamantanyl benzamide &lt;strong&gt;1&lt;/strong&gt; was identified as a potent P2X&lt;sub&gt;7&lt;/sub&gt;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 &lt;strong&gt;1&lt;/strong&gt; 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&lt;sub&gt;7&lt;/sub&gt;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 &lt;strong&gt;34&lt;/strong&gt; demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide &lt;strong&gt;1&lt;/strong&gt;), and an improved physicokinetic profile and proved effective in the presence of several known P2X&lt;sub&gt;7&lt;/sub&gt;R polymorphisms.&lt;/p&gt;</description>
  </descriptions>
  <fundingReferences>
    <fundingReference>
      <funderName>European Commission</funderName>
      <funderIdentifier funderIdentifierType="Crossref Funder ID">10.13039/501100000780</funderIdentifier>
      <awardNumber awardURI="info:eu-repo/grantAgreement/EC/FP7/278850/">278850</awardNumber>
      <awardTitle>Imaging of Neuroinflammation in Neurodegenerative Diseases</awardTitle>
    </fundingReference>
  </fundingReferences>
</resource>
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