Journal
ACS CHEMICAL NEUROSCIENCE
Volume 8, Issue 11, Pages 2374-2380Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.7b00272
Keywords
P2X(7); bioisostere; central nervous system (CNS); pharmacokinetic; metabolism; single nucleotide polymorphisms (SNPs)
Funding
- NHMRC
- European Union's Seventh Framework Programme [FP7] INMiND [HEALTH-F2-2011-278850]
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Adamantanyl benzamide 1 was identified as a potent P2X(7)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 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 P2X(7)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 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 P2X(7)R polymorphisms.
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