N6-Cycloalkyl-2-substituted adenosine derivatives as selective, high affinity adenosine A1 receptor agonists.
A series of new selective, high affinity A(1)-AdoR agonists is reported. Compound 23 that incorporated a carboxylic acid functionality in the 4-position of the pyrazole ring displayed K(iL) value of 1 nM for the A(1)-AdoR and >5000-fold selectivity over the A(3) and A(2A)-AdoRs. In addition, compound 19 that incorporated a carboxamide functionality in the 4-position of the pyrazole ring displayed subnanomolar affinity for the A(1)-AdoR (K(iL)=0.6 nM) and >600-fold selectivity over the A(3) and A(2A)-AdoRs.
Elzein
Elfatih
E
Department of Bioorganic Chemistry, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA. elfatih.elzein@cvt.com
Kalla
Rao
R
Li
Xiaofen
X
Perry
Thao
T
Marquart
Tim
T
Micklatcher
Mark
M
Li
Yuan
Y
Wu
Yuzhi
Y
Zeng
Dewan
D
Zablocki
Jeff
J
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D000960:Hypolipidemic Agents; C519005:N-cyclopentyl-2-(4-carbamoylpyrazol-1-yl)adenosine; C519004:N-norbornyl-2-(4-carboxypyrazol-1-yl)adenosine; D011720:Pyrazoles; D000241:Adenosine