Historical and Current Adenosine Receptor Agonists in Preclinical and Clinical Development

Abstract

Adenosine receptors (ARs) function in the body’s response to conditions of pathology and stress associated with a functional imbalance, such as in the supply and demand of energy/oxygen/nutrients. Extracellular adenosine concentrations vary widely to raise or lower the basal activation of four subtypes of ARs. Endogenous adenosine can correct an energy imbalance during hypoxia and other stress, for example, by slowing the heart rate by A 1 AR activation or increasing the blood supply to heart muscle by the A 2A AR. Moreover, exogenous AR agonists, antagonists, or allosteric modulators can be applied for therapeutic benefit, and medicinal chemists working toward that goal have reported thousands of such agents. Thus, numerous clinical trials have ensued, using promising agents to modulate adenosinergic signaling, most of which have not succeeded. Currently, short-acting, parenteral agonists, adenosine and Regadenoson, are the only AR agonists approved for human use. However, new concepts and compounds are currently being developed and applied toward preclinical and clinical evaluation, and initial results are encouraging. This review focuses on key compounds as AR agonists and positive allosteric modulators (PAMs) for disease treatment or diagnosis. AR agonists for treating inflammation, pain, cancer, non-alcoholic steatohepatitis, angina, sickle cell disease, ischemic conditions and diabetes have been under development. Multiple clinical trials with two A 3 AR agonists are ongoing.

Adenosine Receptor Agonists Exhibit Anti-Platelet Effects and the Potential to Overcome Resistance to P2Y12 Receptor Antagonists

“…Regadenoson (CVT-3146, Lexiscan) is a synthetic AR agonist currently approved for clinical use as a pharmacologic stress agent for myocardial perfusion imaging (MPI). It demonstrates non-inferiority to adenosine for detecting reversible myocardial perfusion defects, although it is a moderately selective (K i = 290 nM), short acting A 2A AR agonist with low affinity for the remaining adenosine receptors [22,25,26]. In addition to its diagnostic application, regadenoson was considered for the treatment of inflammation and sickle cell disease, and was involved in the development of brain tumor-targeted drug delivery systems [27][28][29].…”

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

“…Moreover, this agonist also stimulated A 2B AR, promoting cardioprotection and modulating cardiac fibrosis in heart disease [122]. Unfortunately, the clinical trial of capadenoson was discontinued [123]. A clinical trial using the partial agonist neladenoson (BAY 1067197) for the treatment of heart failure was safe without atrioventricular conduction disorders or neurological adverse effects [124].…”

“…A clinical trial using the partial agonist neladenoson (BAY 1067197) for the treatment of heart failure was safe without atrioventricular conduction disorders or neurological adverse effects [124]. A multiple-dose study of neladenoson in heart failure is still ongoing [123].…”

“…At present, several full A 1 AR agonists have been used in clinical trials as antiarrhythmic agents. An optimal dose of a new A 1 AR selective agonist, tecadenoson (CVT-510), was successful in the conversion of paroxysmal supraventricular tachycardia (PSVT) into sinus rhythm [128], but its development for PSVT and atrial fibrillation (AF) was discontinued in 2009 [123]. Other agonists, such as selodenoson and PJ-875, have started in early phase evaluations for the treatment of AF [129].…”

“…It was assumed that prolonged activation of A 1 AR increased A 2A AR expression, which generated global damage and neurodegeneration in ischemic stroke [135]. Recently, an A 1 AR selective agonist, NNC-21-0136, was designed for neuroprotection in stroke models [123].…”