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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

Hemodynamic responses to increasing doses of compound 2 are dose dependent. Blood pressure (top panel) and heart rate (bottom panel) responses to the first day of intratracheal (i.t.) instillation of compound 2 at 0.1 μg/kg (light grey), 1.0 μg/kg (dotted), 10 μg/kg (dark grey) and vehicle (black) in conscious, telomerized rats demonstrated a major hypotensive response to the highest dose that was normalized within 4 h after dosing. Heart rate was significantly increased during the same time frame for 10 μg/kg vs. the other groups.
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fig09: Hemodynamic responses to increasing doses of compound 2 are dose dependent. Blood pressure (top panel) and heart rate (bottom panel) responses to the first day of intratracheal (i.t.) instillation of compound 2 at 0.1 μg/kg (light grey), 1.0 μg/kg (dotted), 10 μg/kg (dark grey) and vehicle (black) in conscious, telomerized rats demonstrated a major hypotensive response to the highest dose that was normalized within 4 h after dosing. Heart rate was significantly increased during the same time frame for 10 μg/kg vs. the other groups.

Mentions: In the telemetry study, we investigated the effects on blood pressure and HR following repeated once daily i.t. dosing for five consecutive days of compound 2 at 0.1, 1, and 10 μg/kg. Figure9 demonstrates the blood pressure (upper panel) and HR (lower panel) effects after the first day of dosing where 10 μg/kg was the only dose to induce a significant change (P < 0.0001). The interaction between treatment group and time after dose was driven mainly by the high dose group and by the first 4 h after dosing and tells that different treatment groups show different patterns over time after dose.


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)

Hemodynamic responses to increasing doses of compound 2 are dose dependent. Blood pressure (top panel) and heart rate (bottom panel) responses to the first day of intratracheal (i.t.) instillation of compound 2 at 0.1 μg/kg (light grey), 1.0 μg/kg (dotted), 10 μg/kg (dark grey) and vehicle (black) in conscious, telomerized rats demonstrated a major hypotensive response to the highest dose that was normalized within 4 h after dosing. Heart rate was significantly increased during the same time frame for 10 μg/kg vs. the other groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig09: Hemodynamic responses to increasing doses of compound 2 are dose dependent. Blood pressure (top panel) and heart rate (bottom panel) responses to the first day of intratracheal (i.t.) instillation of compound 2 at 0.1 μg/kg (light grey), 1.0 μg/kg (dotted), 10 μg/kg (dark grey) and vehicle (black) in conscious, telomerized rats demonstrated a major hypotensive response to the highest dose that was normalized within 4 h after dosing. Heart rate was significantly increased during the same time frame for 10 μg/kg vs. the other groups.
Mentions: In the telemetry study, we investigated the effects on blood pressure and HR following repeated once daily i.t. dosing for five consecutive days of compound 2 at 0.1, 1, and 10 μg/kg. Figure9 demonstrates the blood pressure (upper panel) and HR (lower panel) effects after the first day of dosing where 10 μg/kg was the only dose to induce a significant change (P < 0.0001). The interaction between treatment group and time after dose was driven mainly by the high dose group and by the first 4 h after dosing and tells that different treatment groups show different patterns over time after dose.

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