title: Structure-affinity relationships of 5'-aromatic ethers and 5'-aromatic sulfides as partial A1 adenosine agonists, potential supraventricular anti-arrhythmic agents.
abstract: Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an estimated 2.3 million cases in the US (2001). A(1) adenosine receptor agonists can slow the electrical impulse propagation through the atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce ventricular rate. Compounds that are full agonists of the A(1) adenosine receptor can cause high grade AV block. Therefore, it is envisioned that a compound that is a partial agonist of the A(1) adenosine receptor could avoid this deleterious effect. 5(') Phenyl sulfides (e.g., 17, EC(50)=1.26 microM) and phenyl ethers (e.g., 28, EC(50)=0.2 microM) are partial agonists with respect to their AV nodal effects in guinea pig isolated hearts. Additional affinity, GTPgammaS binding data suggesting partial activity of the A(1) adenosine receptor, and PK results for 5(') modified adenosine derivatives are shown.
authors.affiliation: Department of Bioorganic Chemistry, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA. chris.morrison@cvt.com
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Morrison
authors.forename: Elfatih
authors.initials: E
authors.lastname: Elzein
authors.forename: Bob
authors.initials: B
authors.lastname: Jiang
authors.forename: Prabha N
authors.initials: PN
authors.lastname: Ibrahim
authors.forename: Timothy
authors.initials: T
authors.lastname: Marquart
authors.forename: Venkata
authors.initials: V
authors.lastname: Palle
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Shenk
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Varkhedkar
authors.forename: Tenning
authors.initials: T
authors.lastname: Maa
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Wu
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Irving
authors.initials: I
authors.lastname: Fong
authors.forename: David
authors.initials: D
authors.lastname: Lustig
authors.forename: Kwan
authors.initials: K
authors.lastname: Leung
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Zablocki
mesh_terms: D000241:Adenosine / Q000378:metabolism; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D001283:Atrioventricular Node / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D002036:Bundle of His / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004987:Ethers / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: D058907:Adenosine A1 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D004987:Ethers; D006841:Hydrocarbons, Aromatic; D043682:Receptor, Adenosine A1; D013440:Sulfides; D000241:Adenosine