Discovery of potent and selective bicyclic A(2B) adenosine receptor antagonists via bioisosteric amide replacement

Paul Eastwood; Jacob Gonzalez; Sergio Paredes; Silvia Fonquerna; Arantxa Cardús; Juan Antonio Alonso; Arsenio Nueda; Teresa Domenech; Raquel F Reinoso; Bernat Vidal

doi:10.1016/j.bmcl.2010.01.077

Discovery of potent and selective bicyclic A(2B) adenosine receptor antagonists via bioisosteric amide replacement

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1634-7. doi: 10.1016/j.bmcl.2010.01.077. Epub 2010 Jan 20.

Authors

Paul Eastwood¹, Jacob Gonzalez, Sergio Paredes, Silvia Fonquerna, Arantxa Cardús, Juan Antonio Alonso, Arsenio Nueda, Teresa Domenech, Raquel F Reinoso, Bernat Vidal

Affiliation

¹ Almirall Research Center, Almirall S.A., Ctra. Laureà Miró 408, E-08980 St. Feliu de Llobregat, Barcelona, Spain. paulroberteastwood@yahoo.co.uk

PMID: 20138516
DOI: 10.1016/j.bmcl.2010.01.077

Abstract

Several new potent and selective A(2B) adenosine receptor antagonists have been prepared in which the aryl-amide moiety of the lead series, exemplified by 1a, has been replaced by bioisosteric bicyclic moieties. Although the majority of compounds had generally improved microsomal stability as compared to 1a, this was not translated into overall improvements in the pharmacokinetic profiles of a representative set of compounds.

MeSH terms

Adenosine A2 Receptor Antagonists*
Amides / chemistry*
Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / pharmacokinetics
Bridged Bicyclo Compounds / chemical synthesis
Bridged Bicyclo Compounds / chemistry*
Bridged Bicyclo Compounds / pharmacokinetics
Drug Discovery
Humans
Microsomes, Liver / metabolism
NADP / metabolism
Rats
Receptor, Adenosine A2B / metabolism

Substances

Adenosine A2 Receptor Antagonists
Amides
Anti-Inflammatory Agents
Bridged Bicyclo Compounds
Receptor, Adenosine A2B
NADP