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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

Increased and repeated doses of compound 2 increases the anti-inflammatory efficacy. Single dosing of compound 2 induced a dose-dependent decrease in the LPS-induced recruitment of neutrophilia to the lung by up to 39% (n.s.) at 10 μg/kg (dark grey bar vs. LPS-challenged controls in black bar). Repeated dosing at 10 μg/kg for 3–5 days increased the efficacy of the compound to a statistically significant effect vs. time-matched controls (not shown) of 53% after 5 days of dosing (P = 0.01). Data are shown as Mean±SEM.
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fig07: Increased and repeated doses of compound 2 increases the anti-inflammatory efficacy. Single dosing of compound 2 induced a dose-dependent decrease in the LPS-induced recruitment of neutrophilia to the lung by up to 39% (n.s.) at 10 μg/kg (dark grey bar vs. LPS-challenged controls in black bar). Repeated dosing at 10 μg/kg for 3–5 days increased the efficacy of the compound to a statistically significant effect vs. time-matched controls (not shown) of 53% after 5 days of dosing (P = 0.01). Data are shown as Mean±SEM.

Mentions: The present study, where three doses (0.1, 1 and 10 μg/kg) were given 24 h prior to the LPS challenge, demonstrated a clear, however not statistically significant, dose–response anti-inflammatory effect by compound 2 (Fig.7, first five bars to the left), giving 9, 17 and 39% inhibition of the recovered neutrophils in the BAL fluid, respectively (P = 0.086 at 10 μg/kg). The baseline levels of recovered cells were normal, however on the low side, thus giving a smaller window for the treatment effect.


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)

Increased and repeated doses of compound 2 increases the anti-inflammatory efficacy. Single dosing of compound 2 induced a dose-dependent decrease in the LPS-induced recruitment of neutrophilia to the lung by up to 39% (n.s.) at 10 μg/kg (dark grey bar vs. LPS-challenged controls in black bar). Repeated dosing at 10 μg/kg for 3–5 days increased the efficacy of the compound to a statistically significant effect vs. time-matched controls (not shown) of 53% after 5 days of dosing (P = 0.01). Data are shown as Mean±SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig07: Increased and repeated doses of compound 2 increases the anti-inflammatory efficacy. Single dosing of compound 2 induced a dose-dependent decrease in the LPS-induced recruitment of neutrophilia to the lung by up to 39% (n.s.) at 10 μg/kg (dark grey bar vs. LPS-challenged controls in black bar). Repeated dosing at 10 μg/kg for 3–5 days increased the efficacy of the compound to a statistically significant effect vs. time-matched controls (not shown) of 53% after 5 days of dosing (P = 0.01). Data are shown as Mean±SEM.
Mentions: The present study, where three doses (0.1, 1 and 10 μg/kg) were given 24 h prior to the LPS challenge, demonstrated a clear, however not statistically significant, dose–response anti-inflammatory effect by compound 2 (Fig.7, first five bars to the left), giving 9, 17 and 39% inhibition of the recovered neutrophils in the BAL fluid, respectively (P = 0.086 at 10 μg/kg). The baseline levels of recovered cells were normal, however on the low side, thus giving a smaller window for the treatment effect.

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