Synthesis and evaluation of two series of 4'-aza-carbocyclic nucleosides as adenosine A2A receptor agonists.
The synthesis of two series of 4'-aza-carbocyclic nucleosides are described in which the 4'-substituent is either a reversed amide, relative to the carboxamide of NECA, or an N-bonded heterocycle. Using established purine substitution patterns, potent and selective examples of agonists of the human adenosine A(2A) receptor have been identified from both series. The propionamides 14-18 and the 4-hydroxymethylpyrazole 32 were determined to be the most potent and selective examples from the 4'-reversed amide and 4'-N-bonded heterocyclic series, respectively.
Beattie
David
D
Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom.
Brearley
Andrew
A
Brown
Zarin
Z
Charlton
Steven J
SJ
Cox
Brian
B
Fairhurst
Robin A
RA
Fozard
John R
JR
Gedeck
Peter
P
Kirkham
Paul
P
Meja
Koremu
K
Nanson
Lana
L
Neef
James
J
Oakman
Helen
H
Spooner
Gillian
G
Taylor
Roger J
RJ
Turner
Robert J
RJ
West
Ryan
R
Woodward
Hannah
H
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011742:Pyrimidine Nucleotides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000378:metabolism
D058908:Adenosine A2 Receptor Agonists; D001372:Aza Compounds; D002264:Carboxylic Acids; D009705:Nucleosides; D011742:Pyrimidine Nucleotides; D043705:Receptor, Adenosine A2A