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.
Highlights
Extracellular adenosine exerts a protective role in conditions of stress, cellular damage and injury via increase of tissue perfusion and associated anti-inflammatory effects
Especially in the coronary vessels (Stepp et al 1996). This effect is due to binding of adenosine to the A2a receptor, and this mechanism is supported by studies with selective A2a agonists (Webb et al 1990, 1991; Matho^t et al 1995; Nekooeian and Tabrizchi 1996)
The present study demonstrates the challenges in achieving a therapeutic window between the beneficial antiinflammatory responses in the lung and the undesired cardiovascular effects even after local lung administration
Summary
Extracellular adenosine exerts a protective role in conditions of stress, cellular damage and injury via increase of tissue perfusion and associated anti-inflammatory effects. These physiological outcomes are the result of activation of four known adenosine receptor subtypes; A1, A2a, A2b, and A3, with all of them being seven transmembrane spanning G-protein coupled receptors (Gessi et al 2011). Especially in the coronary vessels (Stepp et al 1996) This effect is due to binding of adenosine to the A2a receptor, and this mechanism is supported by studies with selective A2a agonists (Webb et al 1990, 1991; Matho^t et al 1995; Nekooeian and Tabrizchi 1996). Lexiscanâ (Regadenoson, Astellas Pharma US, Inc, Northbrook, IL, Fig. 1) is currently the only selective A2a agonist on the market, where its rapid and short-lasting effect is used during radionuclide myocardial perfusion imaging to determine coronary fractional flow reserve (Johnson and Peters 2010; Al Jaroudi and Iskandrian 2012)
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