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A1 adenosine receptor agonists and their potential therapeutic applications
Ist Teil von
Expert opinion on investigational drugs, 2008-12, Vol.17 (12), p.1901-1910
Ort / Verlag
England: Informa UK Ltd
Erscheinungsjahr
2008
Quelle
Taylor & Francis Journals Auto-Holdings Collection
Beschreibungen/Notizen
Background: The challenges in developing any A1 adenosine receptor (A1-AdoR) agonist involve having the desired effect on target tissue while avoiding side effects due to activation of A1-AdoR on other tissues. A1-AdoR de-sensitization leading to tachyphylaxis is also another challenge. Objectives: The major goal of this review is twofold: to highlight the structure affinity relationships (SAR) of A1-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 A1-AdoR agonists under development for various indications. Results: Intense efforts by many pharmaceutical companies and academicians in the A1-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 A1-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 A1-AdoR agonists are in development, including CVT-3619 (hA1-AdoR Ki = 55 nm, selectivity A2A > 200; A2B > 1000; A3 > 20, CV Therapeutics), that have the potential to provide enhanced insulin sensitivity without cardiovascular side effects or tachyphylaxis. The A1-AdoR agonists GW493838 and GR792363 are under evaluation for pain management. The non-nucleosidic A1-AdoR agonist, BAY-68-4986 (Capadenoson), represents a unique approach to angina wherein both animal studies and early human studies are promising. Conclusion: The challenges associated with developing an A1-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.