New highly potent and selective adenosine A(3) receptor antagonists.
A class of potent, selective adenosine A(3) receptor antagonists was obtained via optimisation of the screening hit N-[4-(4-methoxyphenyl)-thiazol-2-yl]-acetamide. Structural modifications of this hit revealed very quickly that a 5-(pyridin-4-yl) substituent on the 2-aminothiazole ring was optimal for high potency at the adenosine A(3) receptor. Structure activity relationship studies led to both potent and selective A(3) receptor antagonists, including N-[5-pyridin-4-yl-4-(3,4,5-trimethoxyphenyl)-thiazol-2-yl]-acetamide, a highly potent aden-osine A(3) receptor antagonist with greater than 100- fold selectivity against the related adenosine receptors. As well as demonstrating selective in vitro binding on the human A(3) adenosine receptor, this compound was also shown to selectively block the rat A(3) receptor in vivo. This important new compound can be readily synthesised in four steps from commercially available starting materials.
Press
Neil J
NJ
Respiratory Disease Area, Novartis Horsham Research Center, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK. neil.press@pharma.novartis.com
Keller
Thomas H
TH
Tranter
Pamela
P
Beer
David
D
Jones
Ken
K
Faessler
Alexander
A
Heng
Richard
R
Lewis
Christine
C
Howe
Trevor
T
Gedeck
Peter
P
Mazzoni
Lazzaro
L
Fozard
John R
JR
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D015195:Drug Design; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000081:Acetamides; D058918:Adenosine A3 Receptor Antagonists; D013844:Thiazoles