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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

Tachycardia and hypotension are observed at increasing concentrations of compound 2 in conscious rats. The effects of four consecutive 15-min intravenous infusions of compound 2 on MAP (A) and HR (B). Plasma concentrations were simulated based on modeling of observed PK data. Individual data are shown with thin coloured lines (A) and mean data (n = 6) are shown with a thick black line (both A and B). Arrows denote time order of measurements.
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fig11: Tachycardia and hypotension are observed at increasing concentrations of compound 2 in conscious rats. The effects of four consecutive 15-min intravenous infusions of compound 2 on MAP (A) and HR (B). Plasma concentrations were simulated based on modeling of observed PK data. Individual data are shown with thin coloured lines (A) and mean data (n = 6) are shown with a thick black line (both A and B). Arrows denote time order of measurements.

Mentions: The relationship between compound 2 plasma concentrations and MAP and HR, respectively, were modeled using data generated in the swivel study. Three of the seven rats demonstrated a HR increase during the first infusion step that was judged as stress or activity related and not associated with the drug infusion, and the data points during the first infusion were discarded for the PK–PD analysis. Hysteresis was observed when individual concentration–MAP response data were plotted in time order (Fig.11). To account for the concentration-effect-time delay an effect-compartment model linked to a decrease in MAP according to a sigmoid Emax model was used to model the data for each individual rat, yielding mean ± SD parameter estimates of 0.058 ± 0.039/min for kE0 (first-order rate constant), 114 ± 6 nmol/L for E0,MAP (the baseline MAP), 37 ± 11 nmol/L for Emax,MAP (the maximum compound 2-induced decrease in MAP), 0.52 ± 0.16 nmol/L for EC50,MAP (the concentration that induces half the maximum MAP decrease) and 1.8 ± 1.1 for n (the Hill factor). HR data were not possible to model on an individual basis with satisfactory fit, but the mean concentration-mean HR response data could be described by a simple Emax model, yielding estimates of 386 nmol/L for E0,HR (the baseline HR), 158 nmol/L for Emax,HR (the maximum compound 2-induced increase in HR) and 0.18 nmol/L for EC50,HR.


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)

Tachycardia and hypotension are observed at increasing concentrations of compound 2 in conscious rats. The effects of four consecutive 15-min intravenous infusions of compound 2 on MAP (A) and HR (B). Plasma concentrations were simulated based on modeling of observed PK data. Individual data are shown with thin coloured lines (A) and mean data (n = 6) are shown with a thick black line (both A and B). Arrows denote time order of measurements.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig11: Tachycardia and hypotension are observed at increasing concentrations of compound 2 in conscious rats. The effects of four consecutive 15-min intravenous infusions of compound 2 on MAP (A) and HR (B). Plasma concentrations were simulated based on modeling of observed PK data. Individual data are shown with thin coloured lines (A) and mean data (n = 6) are shown with a thick black line (both A and B). Arrows denote time order of measurements.
Mentions: The relationship between compound 2 plasma concentrations and MAP and HR, respectively, were modeled using data generated in the swivel study. Three of the seven rats demonstrated a HR increase during the first infusion step that was judged as stress or activity related and not associated with the drug infusion, and the data points during the first infusion were discarded for the PK–PD analysis. Hysteresis was observed when individual concentration–MAP response data were plotted in time order (Fig.11). To account for the concentration-effect-time delay an effect-compartment model linked to a decrease in MAP according to a sigmoid Emax model was used to model the data for each individual rat, yielding mean ± SD parameter estimates of 0.058 ± 0.039/min for kE0 (first-order rate constant), 114 ± 6 nmol/L for E0,MAP (the baseline MAP), 37 ± 11 nmol/L for Emax,MAP (the maximum compound 2-induced decrease in MAP), 0.52 ± 0.16 nmol/L for EC50,MAP (the concentration that induces half the maximum MAP decrease) and 1.8 ± 1.1 for n (the Hill factor). HR data were not possible to model on an individual basis with satisfactory fit, but the mean concentration-mean HR response data could be described by a simple Emax model, yielding estimates of 386 nmol/L for E0,HR (the baseline HR), 158 nmol/L for Emax,HR (the maximum compound 2-induced increase in HR) and 0.18 nmol/L for EC50,HR.

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