The discovery of a selective and potent A_2a agonist with extended lung retention

Abstract

Although the anti-inflammatory role of the A2a receptor is well established, controversy remains with regard to the therapeutic value for A2a agonists in treatment of inflammatory lung diseases, also as a result of unwanted A2a-mediated cardiovascular effects. In this paper, we describe the discovery and characterization of a new, potent and selective A2a agonist (compound 2) with prolonged lung retention and limited systemic exposure following local administration. To support the lead optimization chemistry program with compound selection and profiling, multiple in vitro and in vivo assays were used, characterizing compound properties, pharmacodynamics (PD), and drug concentrations. Particularly, pharmacokinetic-PD modeling was applied to quantify the effects on the cardiovascular system, and an investigative toxicology study in rats was performed to explore potential myocardial toxicities. Compound 2, in comparison to a reference A2a agonist, UK-432,097, demonstrated higher solubility, lower lipophilicity, lower plasma protein binding, high rat lung retention (28% remaining after 24 h), and was efficacious in a lung inflammatory rat model following intratracheal dosing. Despite these properties, compound 2 did not provide a sufficient therapeutic index, that is, separation of local anti-inflammatory efficacy in the lung from systemic side effects in the cardiovascular system. The plasma concentration that resulted in induction of hypotension (half maximal effective concentration; EC50 0.5 nmol/L) correlated to the in vitro A2a potency (rIC50 0.6 nmol/L). Histopathological lesions in the heart were observed at a dose level which is threefold above the efficacious dose level in the inflammatory rat lung model. In conclusion, compound 2 is a highly potent and selective A2a agonist with significant lung retention after intratracheal administration. Despite its local anti-inflammatory efficacy in rat lung, small margins to the cardiovascular effects suggested limited therapeutic value of this compound for treatment of inflammatory lung disease by the inhaled route.

Ocular Purine Receptors as Drug Targets in the Eye

“…However, a range of other G protein-dependent and independent signaling mechanisms are associated with activation of ARs. 1 Nucleoside derivatives that activate ARs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) are shown in Fig. 1, and AR antagonists (both nucleosides and nonnucleosides, 25-49) are shown in Fig.…”

“…17 Potent A 2A AR agonist UK432,097 12 failed clinical trials for COPD, but displays extended lung retention. 18 Lexiscan 13a is a short acting A 2A AR agonist that is approved for dilating coronary vessels during stress testing and was recently demonstrated to open the blood-brain barrier transiently, with a decreased Pglycoprotein expression, and to ameliorate sickle cell disease. [19][20][21] Its A 2A AR affinity and selectivity are only moderate (K i *1.3 mM, >10-fold selective versus A 1 AR).…”

Blood Platelet Adenosine Receptors as Potential Targets for Anti-Platelet Therapy

“…UK-432,094 was tested by PFIZER in a phase II clinical trial (ClinicalTrials.gov Identifier: NCT00430300) as an inhalation agent for severe chronic obstructive pulmonary disease; however, the trial was terminated due to low treatment effectiveness. UK-432094 is a selective A 2A agonist (Ki of 4.75 nM) [108], with reported EC 50 as low as 5.4 ±1.8 nM (cAMP level evaluation in CHO cells stably expressing human A 2A and A 2B receptors) [109]. Its anti-platelet effect has been recently assessed using multiple electric aggregometry in whole blood.…”

Safety issues of compounds acting on adenosinergic signalling

“…Recent investigative toxicology study of a potent and selective A 2A AdR agonist for potential treatment of inflammatory lung diseases showed cardiotoxic response. Single‐dose rat study (150 μg/kg) revealed myocardial necrosis with several foci together with perivascular and ventricular oedema, whereas during repeated dose study (30 μg/kg per 4 days) fibrotic heart tissue has developed . Mechanisms of cardiovascular toxicity still remain uncertain but appear to be partly related to excessive induction of endothelial nitric oxide synthase .…”

“…Single-dose rat study (150 lg/kg) revealed myocardial necrosis with several foci together with perivascular and ventricular oedema, whereas during repeated dose study (30 lg/kg per 4 days) fibrotic heart tissue has developed. [119] Mechanisms of cardiovascular toxicity still remain uncertain but appear to be partly related to excessive induction of endothelial nitric oxide synthase. [120] It was also suggested from multiple sources that some antidepressants (citalopram, amitriptyline) may cause QRS/QT prolongation activating A 1 AdRs.…”