title: A1 adenosine receptor agonists and their potential therapeutic applications.
abstract: BACKGROUND
  The challenges in developing any A(1) adenosine receptor (A(1)-AdoR) agonist involve having the desired effect on target tissue while avoiding side effects due to activation of A(1)-AdoR on other tissues. A(1)-AdoR de-sensitization leading to tachyphylaxis is also another challenge.
  
  
  OBJECTIVE
  The major goal of this review is twofold: to highlight the structure affinity relationships (SAR) of A(1)-AdoR agonists, starting with initial lead compounds that were the genesis for second-generation compounds with high selectivity, affinity, and partial agonism; and to give an overview of the A(1)-AdoR agonists under development for various indications.
  
  
  RESULTS
  Intense efforts by many pharmaceutical companies and academicians in the A(1)-AdoR agonist field have led to the discovery of clinical candidates for the following conditions: atrial arrhythmias - Tecadenoson, Selodenoson and PJ-875; type 2 diabetes (T2D) and insulin-sensitizing agents - GR79236, ARA, and CVT-3619; pain management - SDZ WAG 994, GW493838; and angina - BAY-68-4986. For the i.v. antiarrhythmic agents that act as ventricular rate control agents, a selective response can be accomplished by careful dosing paradigms. The treatment of T2D using A(1)-AdoR agonists has been met by limited success due to cardiovascular side effects and well-defined desensitization of full agonists in both animal models and human trials (GR79236 and ARA). However, new partial A(1)-AdoR agonists are in development, including CVT-3619 (hA(1)-AdoR K(i) = 55 nm, selectivity A(2A) > 200; A(2B) > 1000; A(3) > 20, CV Therapeutics), that have the potential to provide enhanced insulin sensitivity without cardiovascular side effects or tachyphylaxis. The A(1)-AdoR agonists GW493838 and GR792363 are under evaluation for pain management. The non-nucleosidic A(1)-AdoR agonist, BAY-68-4986 (Capadenoson), represents a unique approach to angina wherein both animal studies and early human studies are promising.
  
  
  CONCLUSIONS
  The challenges associated with developing an A(1)-AdoR agonist for therapeutic intervention are now well defined in humans. Significant progress has been made in identifying agents for the treatment of atrial arrhythmias, T2D, and angina.
authors.affiliation: CV Therapeutics, Inc., Department of Bioorganic Chemistry, 3172 Porter Drive, Palo Alto, CA 94304, USA.
authors.forename: Elfatih
authors.initials: E
authors.lastname: Elzein
authors.forename: Jeff
authors.initials: J
authors.lastname: Zablocki
mesh_terms: D058907:Adenosine A1 Receptor Agonists; D000631:Aminopyridines; D000787:Angina Pectoris / Q000188:drug therapy; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007328:Insulin / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D013844:Thiazoles
chemical_list: D058907:Adenosine A1 Receptor Agonists; D000631:Aminopyridines; D000889:Anti-Arrhythmia Agents; D007328:Insulin; D043682:Receptor, Adenosine A1; D013844:Thiazoles; C575871:capadenoson