Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X 7 Receptor Antagonist

Adamantanyl benzamide 1 was identified as a potent P2X 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 inv...

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Bibliographic Details
Published in:ACS chemical neuroscience 2017-11, Vol.8 (11), p.2374-2380
Main Authors: 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
Format: Article
Language:English
Subjects:
Adamantane - analogs & derivatives
Adamantane - pharmacology
Animals
Benzamides - chemical synthesis
Benzamides - chemistry
Benzamides - pharmacokinetics
Benzamides - pharmacology
Biotransformation
Drug Evaluation, Preclinical
Drug Stability
Humans
Microsomes, Liver - metabolism
Molecular Structure
Oxidation-Reduction
Polymorphism, Single Nucleotide
Purinergic P2X Receptor Antagonists - chemical synthesis
Purinergic P2X Receptor Antagonists - chemistry
Purinergic P2X Receptor Antagonists - pharmacokinetics
Purinergic P2X Receptor Antagonists - pharmacology
Rats
Receptors, Purinergic P2X7 - drug effects
Receptors, Purinergic P2X7 - genetics
Structure-Activity Relationship
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Description
Summary:Adamantanyl benzamide 1 was identified as a potent P2X 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 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 R polymorphisms.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.7b00272