A1 adenosine receptor antagonists, agonists, and allosteric enhancers

Abstract

Intense efforts of many pharmaceutical companies and academicians in the A1 adenosine receptor (AR) field have led to the discovery of clinical candidates that are antagonists, agonists, and allosteric enhancers. The A1AR antagonists currently in clinical development are KW3902, BG9928, and SLV320. All three have high affinity for the human (h) A 1AR subtype (hA1 K i < 10 nM), > 200-fold selectivity over the hA2A subtype, and demonstrate renal protective effects in multiple animal models of disease and pharmacologic effects in human subjects. In the A1AR agonist area, clinical candidates have been discovered for the following conditions: atrial arrhythmias (tecadenoson, selodenoson and PJ-875); Type II diabetes and insulin sensitizing agents (GR79236, ARA, RPR-749, and CVT-3619); and angina (BAY 68-4986). The challenges associated with the development of any A1AR agonist are to obtain tissue-specific effects but avoid off-target tissue side effects and A 1AR desensitization leading to tachyphylaxis. For the IV antiarrhythmic agents that act as ventricular rate control agents, a selective response can be accomplished by careful IV dosing paradigms. The treatment of type II diabetes using A1AR agonists in the clinic has met with limited success due to cardiovascular side effects and a well-defined desensitization of full agonists in human trials (GR79236, ARA, and RPR 749). However, new partial A1AR agonists are in development, including CVT-3619 \,200> :1,000:20, CV Therapeutics), which have the potential to provide enhanced insulin sensitivity without cardiovascular side effects and tachyphylaxis. The nonnucleosidic A1AR agonist BAY 68-4986 (capadenoson) represents a novel approach to angina wherein both animal studies and early human studies are promising. T-62 is an A1AR allosteric enhancer that is currently being evaluated in clinical trials as a potential treatment for neuropathic pain. The challenges associated with developing A 1AR antagonists, agonists, or allosteric enhancers for therapeutic intervention are now well defined in humans. Significant progress has been made in identifying A1AR antagonists for the treatment of edema associated with congestive heart failure (CHF), A1AR agonists for the treatment of atrial arrhythmias, type II diabetes and angina, and A1AR allosteric enhancers for the treatment of neuropathic pain. © 2009 Springer-Verlag Berlin Heidelberg.