Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist

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 inv...

Full description

Saved in:
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
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.7b00272