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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    <subfield code="a">Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist</subfield>
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    <subfield code="a">&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;</subfield>
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