Bioorg Med Chem Lett. 2004 Jan;14(2):535-539.
Affinity and intrinsic efficacy (IE) of 5'-carbamoyl adenosine analogues for the A(1) adenosine receptor-efforts towards the discovery of a chronic ventricular rate control agent for the treatment of atrial fibrillation (AF).
Palle VP, Varkhedkar V, Ibrahim P, Ahmed H, Li Z, Gao Z, Ozeck M, Wu Y, Zeng D, Wu L, Leung K, Chu N, Zablocki JA.
Department of Bioorganic Chemistry, CV Therapeutics, 3172 Porter Drive, CA 94304, Palo Alto, USA
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). |
