Affinity and intrinsic efficacy (IE) of 5'-carbamoyl adenosine analogues for the A1 adenosine receptor--efforts towards the discovery of a chronic ventricular rate control agent for the treatment of atrial fibrillation (AF).
The SAR for the affinity to the A(1) adenosine receptor and relative intrinsic efficacy (IE, [(35)S]-GTPgammaS binding) of a series of 5'-carbamate and 5'-thionocarbamate derivatives of tecadenoson is described. Based on this SAR, selected compounds were evaluated in guinea pig isolated hearts to determine whether they were partial or full agonists with respect to their negative dromotropism, an A(1) AdoR mediated effect. Progress towards obtaining a partial A(1) AdoR agonist to potentially control ventricular rate during atrial fibrillation has been made with the discovery of several potent partial A(1) AdoR agonists (compounds 13, 14, and 17).
Palle
Venkata P
VP
Department of Bioorganic Chemistry, CV Therapeutics, 3172 Porter Drive, Palo Alto, CA 94304, USA.
Varkhedkar
Vaibhav
V
Ibrahim
Prabha
P
Ahmed
Hiba
H
Li
Zhihe
Z
Gao
Zhenhai
Z
Ozeck
Mark
M
Wu
Yuzhi
Y
Zeng
Dewan
D
Wu
Lin
L
Leung
Kwan
K
Chu
Nancy
N
Zablocki
Jeff A
JA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D043682:Receptor, Adenosine A1; D000241:Adenosine