Pharmacological evaluation of a novel series of urea, thiourea and guanidine derivatives as P2X7 receptor antagonists

Erick C N Wong; Tristan A Reekie; Eryn L Werry; James O'Brien-Brown; Sarah L Bowyer; Michael Kassiou

doi:10.1016/j.bmcl.2017.04.005

Pharmacological evaluation of a novel series of urea, thiourea and guanidine derivatives as P2X₇ receptor antagonists

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2439-2442. doi: 10.1016/j.bmcl.2017.04.005. Epub 2017 Apr 4.

Authors

Erick C N Wong¹, Tristan A Reekie², Eryn L Werry³, James O'Brien-Brown², Sarah L Bowyer², Michael Kassiou⁴

Affiliations

¹ School of Medical Sciences, The University of Sydney, NSW 2006, Australia.
² School of Chemistry, The University of Sydney, NSW 2006, Australia.
³ Faculty of Health Sciences, The University of Sydney, NSW 2006, Australia.
⁴ School of Chemistry, The University of Sydney, NSW 2006, Australia. Electronic address: michael.kassiou@sydney.edu.au.

PMID: 28408229
DOI: 10.1016/j.bmcl.2017.04.005

Abstract

We report on P2X₇ receptor antagonists based on a lead adamantly-cyanoguanidine-aryl moiety. We have investigated the importance of the central cyanoguanidine moiety by replacing it with urea, thiourea or guanidine moieties. We have also investigated the linker length between the central moiety and the aryl portion. All compounds were assessed for their inhibitory potency in a pore-formation dye uptake assay at the P2X₇ receptor. None of the compounds resulted in an improved potency illustrating the importance of the cyanoguanidine moiety in this chemotype.

Keywords: Cyanoguanidine; Inflammation; P2X(7)R; Thiourea; Urea.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adamantane / analogs & derivatives
Adamantane / chemistry
Adenosine Triphosphate / analogs & derivatives
Adenosine Triphosphate / pharmacology
Benzoxazoles / metabolism
Cell Line
Fluorescent Dyes / metabolism
Guanidines / chemistry
Guanidines / pharmacology*
Humans
Molecular Structure
Purinergic P2X Receptor Agonists / pharmacology
Purinergic P2X Receptor Antagonists / chemistry
Purinergic P2X Receptor Antagonists / pharmacology*
Quinolinium Compounds / metabolism
Thiourea / analogs & derivatives*
Thiourea / chemistry
Thiourea / pharmacology*
Urea / analogs & derivatives*
Urea / chemistry
Urea / pharmacology*

Substances

Benzoxazoles
Fluorescent Dyes
Guanidines
Purinergic P2X Receptor Agonists
Purinergic P2X Receptor Antagonists
Quinolinium Compounds
YO-PRO 1
3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate
Adenosine Triphosphate
Urea
Thiourea
Adamantane