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.

Rationale and design of the phase 2b clinical trials to study the effects of the partial adenosine A1‐receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced (PANTHEON) and preserved (PANACHE) ejection fraction

“…Neladenoson bialanate (BAY 1067197, which is the free base of the hydrochloride BAY 86-8901) is the prodrug of the pharmacologically active compound neladenoson (BAY 84-3174), a highly potent and selective non-adenosine-like partial adenosine A1-receptor agonist suitable for once daily oral use. 7,8 The reason for the development of a partial adenosine A1-receptor agonist is that the use of full A1-receptor agonists in HF has been limited by undesirable cardiac effects such as negative inotropic, chronotropic, and dromotropic effects, including high-degree atrioventricular (AV) block, in particular with the concomitant use of -blockers. 8 In addition, a full agonist might have undesired extracardiac effects such as anti-diuretic effects (caused by vasoconstriction of the renal afferent arterioles) and neurological effects such as sedation.…”

“…Partial adenosine A1-receptor agonists can also normalize the disturbed SERCA2a protein levels in HF models, and thereby potentially improve the activity of the SERCA2a calcium pump. 7 In patients with HF, the normal, orderly transport of calcium ions in and out of the sarcoplasmic reticulum is dysregulated for several reasons, including dysfunction of SERCA2a. 9 In preclinical studies of HF, treatment with the partial adenosine A1-receptor agonist capadenoson prevented the decline in SERCA2a activity that was observed in the untreated control group.…”

“…In addition, a full agonist might have undesired extracardiac effects such as anti‐diuretic effects (caused by vasoconstriction of the renal afferent arterioles) and neurological effects such as sedation. A partial adenosine A1‐receptor agonist might overcome these undesired side effects while preserving the potentially beneficial cardioprotective effects of adenosine, depending on the tissue‐specific receptor reserve for determined pharmacological effects and on the effects of endogenous adenosine …”

Safety and efficacy of the partial adenosine A1 receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced ejection fraction: a phase IIb, randomized, double‐blind, placebo‐controlled trial

“…Adenosine is ubiquitously present in the entire body and is activated in response to stress to protect against organ and tissue damage. In the heart, activation of adenosine A1 receptors modulates ischaemic injury, arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodelling . Heart failure (HF) with reduced ejection fraction (HFrEF) is characterized by impaired mitochondrial function and impaired calcium handling due to a decreased activity of sarcoplasmic reticulum Ca 2+ ‐ATPase (SERCA2a).…”

“…Partial agonists might limit the undesired cardiac conduction disorders and renal effects while preserving beneficial effects on the heart. Preclinical studies showed that a partial adenosine A1 receptor agonist improved cardiac function at doses that did not have undesirable effects on heart rate, AV conduction, and blood pressure . The safety and tolerability of the partial adenosine A1 receptor agonist neladenoson bialanate was studied in two small pilot studies in patients with HFrEF .…”