Pharmacological evaluation of novel bioisosteres of an adamantanyl benzamide P2X7 receptor antagonist

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

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Adamantanyl benzamide 1 was identified as a potent P2X7R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 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 P2X7R 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 34 demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide 1), and an improved physicokinetic profile and proved effective in the presence of several known P2X7R polymorphisms.

Original languageEnglish
Pages (from-to)2374–2380
Number of pages7
JournalACS Chemical Neuroscience
Issue number11
Early online date25 Aug 2017
Publication statusPublished - 15 Nov 2017

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