Design and application of locally delivered agonists of the adenosine A_2Areceptor

Abstract

The broad spectrum anti-inflammatory actions of adenosine A(2A) receptor agonists are well described. The wide distribution of this receptor, however, suggests that the therapeutic potential of these agents is likely to reside in topical treatments to avoid systemic side effects associated with oral administration. Adenosine A(2A) receptor agonists have been assessed as topical agents: GW328267X (GSK; allergic rhinitis and asthma), UK-432097 (Pfizer; chronic obstructive pulmonary disease [COPD]) and Sonedenoson (MRE0094, King Pharmaceuticals; wound healing). All trials failed to achieve effects against the desired clinical end points. This broad-based review will discuss general principles of chemical design of topically applied agents and potential therapeutic topical applications of current adenosine A(2A) receptor agonists. Potential factors contributing to the lack of efficacy in the above clinical trials will be discussed together with design principles, which may influence efficacy in disease states. Our analysis suggests that adenosine A(2A) receptor agonists have a wide therapeutic potential as topical agents in a wide variety of diseases, such as neutrophil-dependent lung diseases (acute lung injury, exacerbations in asthma and COPD), allergic rhinitis, glaucoma and wound repair. Factors that will influence topical activity include formulation, tissue retention, compound potency, receptor kinetics and pharmacokinetics.

Structure-Activity Relationships of the Sustained Effects of Adenosine A2A Receptor Agonists Driven by Slow Dissociation Kinetics

“…The A2A-selective agonist regadenoson is used clinically as a pharmacological stress agent for myocardial imaging (Chen et al, 2013). A2A agonists have anti-inflammatory properties and are thus targeted for the potential treatment of chronic obstructive pulmonary disease, asthma, allergic rhinitis, sickle cell disease, and wound healing, among others, with a number of compounds (e.g., UK-432,097; compound 3cd in Table 1) reaching clinical trials (Mantell et al, 2010; Field et al, 2013). The A2A agonist BVT.115959 has also been in trials for diabetic neuropathic pain (Gao and Jacobson, 2011).…”

“…To achieve a better safety profile, short-lived activity has been optimized for ligands developed as intravenous myocardial imaging agents (Cerqueira, 2004). On the other hand, A2A agonists developed for the treatment of chronic inflammatory diseases, such as UK-432,097, have been targeted for local drug delivery to minimize side effects (Mantell et al, 2010). A long duration of target activity alongside appropriate physicochemical properties to aid tissue retention has been suggested to help achieve efficacy through topical application (Mantell et al, 2010).…”

“…On the other hand, A2A agonists developed for the treatment of chronic inflammatory diseases, such as UK-432,097, have been targeted for local drug delivery to minimize side effects (Mantell et al, 2010). A long duration of target activity alongside appropriate physicochemical properties to aid tissue retention has been suggested to help achieve efficacy through topical application (Mantell et al, 2010). Therefore, for A2A drug discovery programs it is critical to increase our understanding of the temporal response profiles of drug candidates and the mechanisms through which long/short duration of action can occur.…”

“…Optimizing ligand binding kinetics has been advocated as a valuable strategy for achieving appropriate duration of action and target coverage (Copeland et al, 2006; Guo et al, 2014; Hothersall et al, 2016). Specifically, slow A2A agonist dissociation kinetics have been cited as a potential mechanism to achieve a desirable clinical response for topically applied drugs (Mantell et al, 2010). This approach may be especially relevant for A2A where the receptor has been shown to signal without agonists inducing desensitization and internalization in recombinant systems as well as in physiologic settings (Abbracchio et al, 1992; Adami et al, 1995; Charalambous et al, 2008; Zezula and Freissmuth, 2008; Baines et al, 2011), so long-lived agonist responses are possible.…”

Exciting directions in glaucoma

“…(29) Novel adenosine A 2a receptor agonist OPA-6566 (Acucela and Otsuka Pharmaceuticals) is thought to lower IOP in human patients by stimulating aqueous humor outflow via the TM (30). A 2A receptors mediate vasodilatation, coupling through G proteins to stimulate adenylyl cyclase, and may be down-regulated after chronic exposure to an agonist (31, 32). A 3 / A 1 receptor agonist CF-101 (Can-Fite BioPharma) is an orally administered compound that showed IOP lowering efficacy in a phase II clinical trial aimed at reducing symptoms of dry eye (33).…”