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The discovery of a selective and potent A2a agonist with extended lung retention.

Åstrand AB, Lamm Bergström E, Zhang H, Börjesson L, Söderdahl T, Wingren C, Jansson AH, Smailagic A, Johansson C, Bladh H, Shamovsky I, Tunek A, Drmota T - Pharmacol Res Perspect (2015)

Bottom Line: 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).In conclusion, compound 2 is a highly potent and selective A2a agonist with significant lung retention after intratracheal administration.

View Article: PubMed Central - PubMed

Affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

Twenty-four hours pre-treatment optimizes the anti-inflammatory effect by compound 2 given i.t. Amount of neutrophils in BAL fluid in saline-treated (open circles), LPS-challenged (closed circles) and compound 2-treated rats at 10 μg/kg; 36 h (open triangles), 24 h (open diamonds) or 12 h (open squares) prior to the LPS challenge. Data is shown as individual values with group averages as a dash.
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fig06: Twenty-four hours pre-treatment optimizes the anti-inflammatory effect by compound 2 given i.t. Amount of neutrophils in BAL fluid in saline-treated (open circles), LPS-challenged (closed circles) and compound 2-treated rats at 10 μg/kg; 36 h (open triangles), 24 h (open diamonds) or 12 h (open squares) prior to the LPS challenge. Data is shown as individual values with group averages as a dash.

Mentions: LPS induced a significant increase of neutrophils in the rat BAL fluid 24 h after LPS challenge (Fig.6). Previous dose–response studies with compound 2 had demonstrated that a single i.t. dose of 10 μg/kg inhibited neutrophil recruitment in rodents to a maximum (corresponding to 40–50% inhibition). Prophylactic treatment with compound 2 at 10 μg/kg showed a significant reduction of both total cells and neutrophilia in the BAL fluid with 36 and 24 h pre-treatment, whereas with 12 h pretreatment the effect was not significant (Fig.6). Therefore, a pretreatment time of 24 h was used for the upcoming studies.


The discovery of a selective and potent A2a agonist with extended lung retention.

Åstrand AB, Lamm Bergström E, Zhang H, Börjesson L, Söderdahl T, Wingren C, Jansson AH, Smailagic A, Johansson C, Bladh H, Shamovsky I, Tunek A, Drmota T - Pharmacol Res Perspect (2015)

Twenty-four hours pre-treatment optimizes the anti-inflammatory effect by compound 2 given i.t. Amount of neutrophils in BAL fluid in saline-treated (open circles), LPS-challenged (closed circles) and compound 2-treated rats at 10 μg/kg; 36 h (open triangles), 24 h (open diamonds) or 12 h (open squares) prior to the LPS challenge. Data is shown as individual values with group averages as a dash.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492750&req=5

fig06: Twenty-four hours pre-treatment optimizes the anti-inflammatory effect by compound 2 given i.t. Amount of neutrophils in BAL fluid in saline-treated (open circles), LPS-challenged (closed circles) and compound 2-treated rats at 10 μg/kg; 36 h (open triangles), 24 h (open diamonds) or 12 h (open squares) prior to the LPS challenge. Data is shown as individual values with group averages as a dash.
Mentions: LPS induced a significant increase of neutrophils in the rat BAL fluid 24 h after LPS challenge (Fig.6). Previous dose–response studies with compound 2 had demonstrated that a single i.t. dose of 10 μg/kg inhibited neutrophil recruitment in rodents to a maximum (corresponding to 40–50% inhibition). Prophylactic treatment with compound 2 at 10 μg/kg showed a significant reduction of both total cells and neutrophilia in the BAL fluid with 36 and 24 h pre-treatment, whereas with 12 h pretreatment the effect was not significant (Fig.6). Therefore, a pretreatment time of 24 h was used for the upcoming studies.

Bottom Line: 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).In conclusion, compound 2 is a highly potent and selective A2a agonist with significant lung retention after intratracheal administration.

View Article: PubMed Central - PubMed

Affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus