Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist
Authors/Creators
- 1. School of Chemistry, The University of Sydney, NSW 2006 (Australia)
- 2. Faculty of Health Sciences, The University of Sydney, NSW 2006 (Australia)
- 3. Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, De Boelelaan 1117 (The Netherlands)
- 4. School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ (UK)
- 5. Pharmidex, 14 Hanover St, Mayfair, London W1S 1YH (UK)
- 6. Sydney Medical School Nepean, The University of Sydney, NSW 2006 (Australia)
- 7. Faculty of Pharmacy, The University of Sydney, NSW 2006 (Australia)
Description
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.
Files
Wilkinson_ACSChemNeuro_2017-P19-AAM.pdf
Files
(708.5 kB)
| Name | Size | Download all |
|---|---|---|
|
md5:c1394df823897a12d3af2225a44c57a9
|
708.5 kB | Preview Download |