Synthesis and SAR studies of trisubstituted purinones as potent and selective adenosine A2A receptor antagonists

Yuefei Shao; Andrew G Cole; Marc-Raleigh Brescia; Lan-Ying Qin; Jingqi Duo; Tara M Stauffer; Laura L Rokosz; Brian F McGuinness; Ian Henderson

doi:10.1016/j.bmcl.2009.01.042

Synthesis and SAR studies of trisubstituted purinones as potent and selective adenosine A2A receptor antagonists

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1399-402. doi: 10.1016/j.bmcl.2009.01.042. Epub 2009 Jan 19.

Authors

Yuefei Shao¹, Andrew G Cole, Marc-Raleigh Brescia, Lan-Ying Qin, Jingqi Duo, Tara M Stauffer, Laura L Rokosz, Brian F McGuinness, Ian Henderson

Affiliation

¹ Pharmacopeia, Inc., PO Box 5350, Princeton, NJ 08543, USA.

PMID: 19181527
DOI: 10.1016/j.bmcl.2009.01.042

Abstract

A series of trisubstituted purinones was synthesized and evaluated as A(2A) receptor antagonists. The A(2A) structure-activity relationships at the three substituted positions were studied and selectivity against the A(1) receptor was investigated. One antagonist 12o exhibits a K(i) of 9nM in an A(2A) binding assay, a K(b) of 18nM in an A(2A) cAMP functional assay, and is 220-fold selective over the A(1) receptor.

Publication types

Comparative Study

MeSH terms

Adenosine A2 Receptor Antagonists*
Animals
Humans
Protein Binding / drug effects
Protein Binding / physiology
Purinones / chemical synthesis*
Purinones / metabolism
Purinones / pharmacology
Rats
Receptor, Adenosine A2A / metabolism
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / metabolism
Structure-Activity Relationship

Substances

Adenosine A2 Receptor Antagonists
Purinones
Receptor, Adenosine A2A
Recombinant Proteins