Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists

James O'Brien-Brown; Alexander Jackson; Tristan A Reekie; Melissa L Barron; Eryn L Werry; Paolo Schiavini; Michelle McDonnell; Lenka Munoz; Shane Wilkinson; Benjamin Noll; Shudong Wang; Michael Kassiou

doi:10.1016/j.ejmech.2017.02.060

Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X₇ receptor antagonists

Eur J Med Chem. 2017 Apr 21:130:433-439. doi: 10.1016/j.ejmech.2017.02.060. Epub 2017 Mar 2.

Affiliations

¹ School of Chemistry, The University of Sydney, NSW, 2006, Australia.
² School of Medical Sciences, The University of Sydney, NSW, 2006, Australia.
³ Faculty of Health Sciences, The University of Sydney, NSW, 2006, Australia.
⁴ Charles Perkins Centre, The University of Sydney, NSW, 2006, Australia.
⁵ School of Pharmacy and Medical Sciences, University of South Australia, SA, 5001, Australia.
⁶ School of Chemistry, The University of Sydney, NSW, 2006, Australia. Electronic address: michael.kassiou@sydney.edu.au.

PMID: 28279849
DOI: 10.1016/j.ejmech.2017.02.060

Abstract

Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1β release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X₇R antagonists.

Keywords: ATP; Adamantane; Adamantyl; Alzheimer's; IL-1β; Inflammation; Neurodegenerative; P2X receptor; P2X(7)R antagonist.

MeSH terms

Adamantane / chemistry
Adamantane / pharmacology*
Animals
Antidepressive Agents / chemistry*
Antidepressive Agents / pharmacology
Behavior / drug effects
Drug Discovery
Guanidines / chemistry
Guanidines / pharmacology*
Mice
Purinergic P2X Receptor Antagonists / chemistry*
Purinergic P2X Receptor Antagonists / pharmacology
Structure-Activity Relationship

Substances

Antidepressive Agents
Guanidines
Purinergic P2X Receptor Antagonists
dicyandiamido
Adamantane