bay-68-4986 and Angina-Pectoris

Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra-cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R-mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Aminopyridines; Angina Pectoris; Animals; Anti-Arrhythmia Agents; Coronary Artery Disease; Diabetes Mellitus; Dipeptides; Drug Partial Agonism; Furans; Heart; Heart Failure; Humans; Insulin Resistance; Ischemic Preconditioning, Myocardial; Lipolysis; Mitochondria, Heart; Myocardium; Oxygen Consumption; Pyridines; Renal Insufficiency; Tachycardia, Supraventricular; Thiazoles

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.. 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.. 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.. 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.

Topics: Adenosine A1 Receptor Agonists; Aminopyridines; Angina Pectoris; Animals; Anti-Arrhythmia Agents; Humans; Insulin; Pain; Receptor, Adenosine A1; Thiazoles