Structure-affinity relationships of 5'-aromatic ethers and 5'-aromatic sulfides as partial A1 adenosine agonists, potential supraventricular anti-arrhythmic agents.
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.
Morrison
Christopher F
CF
Department of Bioorganic Chemistry, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA. chris.morrison@cvt.com
Elzein
Elfatih
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Jiang
Bob
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Ibrahim
Prabha N
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Marquart
Timothy
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Palle
Venkata
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Shenk
Kevin D
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Varkhedkar
Vaibhav
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Maa
Tenning
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Wu
Lin
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Wu
Yuzhi
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Zeng
Dewan
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Fong
Irving
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Lustig
David
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Leung
Kwan
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Zablocki
Jeff A
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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
D058907:Adenosine A1 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D004987:Ethers; D006841:Hydrocarbons, Aromatic; D043682:Receptor, Adenosine A1; D013440:Sulfides; D000241:Adenosine