title: 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).
abstract: 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).
authors.affiliation: Department of Bioorganic Chemistry, CV Therapeutics, 3172 Porter Drive, Palo Alto, CA 94304, USA.
authors.forename: Venkata P
authors.initials: VP
authors.lastname: Palle
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Varkhedkar
authors.forename: Prabha
authors.initials: P
authors.lastname: Ibrahim
authors.forename: Hiba
authors.initials: H
authors.lastname: Ahmed
authors.forename: Zhihe
authors.initials: Z
authors.lastname: Li
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Gao
authors.forename: Mark
authors.initials: M
authors.lastname: Ozeck
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Wu
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Kwan
authors.initials: K
authors.lastname: Leung
authors.forename: Nancy
authors.initials: N
authors.lastname: Chu
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Zablocki
mesh_terms: 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
chemical_list: D043682:Receptor, Adenosine A1; D000241:Adenosine