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|Title:||Pharmacological evaluation of novel bioisosteres of an adamantanyl benzamide P2₇ receptor antagonist|
|Other Titles:||Pharmacological evaluation of novel bioisosteres of an adamantanyl benzamide P2(7) receptor antagonist|
|Citation:||ACS Chemical Neuroscience, 2017; 8(11):2374-2380|
|Publisher:||American Chemical Society|
|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, and Michael Kassiou|
|Abstract:||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.|
|Keywords:||P2X₇; bioisostere; central nervous system (CNS); pharmacokinetic; metabolism; single nucleotide polymorphisms (SNPs)|
|Description:||Published: August 25, 2017|
|Rights:||© 2017 American Chemical Society|
|Appears in Collections:||Aurora harvest 8|
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