title: Partial Adenosine A1 Agonist in Heart Failure.
abstract: 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.
authors: Department of Cardiology, HELIOS Clinic Wuppertal, University Hospital Witten/Herdecke, Wuppertal, Germany. Wilfried.dinh@bayer.com.|Drug Discovery, Clinical Sciences, Experimental Medicine, Bayer Pharma AG, Wuppertal, Germany. Wilfried.dinh@bayer.com.
authors: Wilfried
authors: W
authors: Dinh
authors: Drug Discovery, Department of Heart Diseases, Bayer Pharma AG Research Center, Wuppertal, Germany.|Department of Medicinal Chemistry, Bayer Pharma AG Research Center, Wuppertal, Germany.
authors: Barbara
authors: B
authors: Albrecht-Küpper
authors: Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 201 East Huron, Galter 3-150, Chicago, IL, 60601, USA.
authors: Mihai
authors: M
authors: Gheorghiade
authors: Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Adriaan A
authors: AA
authors: Voors
authors: Bayer Pharma AG, Wuppertal, Germany.
authors: Michael
authors: M
authors: van der Laan
authors: Division of Cardiovascular Medicine, Department of Medicine, Henry Ford Hospital, Detroit, MI, USA.
authors: Hani N
authors: HN
authors: Sabbah
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use; D000787:Angina Pectoris / Q000188:drug therapy; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D003324:Coronary Artery Disease; D003920:Diabetes Mellitus; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use; D054333:Drug Partial Agonism; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007333:Insulin Resistance; D019157:Ischemic Preconditioning, Myocardial; D008066:Lipolysis / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051437:Renal Insufficiency; D013617:Tachycardia, Supraventricular / Q000188:drug therapy; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D058907:Adenosine A1 Receptor Agonists; D000631:Aminopyridines; D000889:Anti-Arrhythmia Agents; D004151:Dipeptides; D005663:Furans; D011725:Pyridines; D013844:Thiazoles; C000623125:neladenoson bialanate; C522396:selodenoson; C118601:tecadenoson; D000241:Adenosine; C575871:capadenoson
keywords: Adenosine; Adenosine A1 receptor; Adenylate cyclase; Heart failure; Neladenoson