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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 comes before hypotension as the plasma concentration of compound 2 increases. Blood pressure (white bars) and heart rate (black bars) in 6 conscious rats during a 4-step intravenous escalating design (Dose 1–4, equivalent to 1.9, 11, 67, and 410 μg/kg per min) followed by 120 min of washout (WO 10–120) demonstrated baroreflex-compensated hypotension in response to compound 2. The dotted and solid lines represent an untreated time-match control rat in the same setting. Data are Mean±SEM for the last 5 min at each dose level.
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fig08: Tachycardia comes before hypotension as the plasma concentration of compound 2 increases. Blood pressure (white bars) and heart rate (black bars) in 6 conscious rats during a 4-step intravenous escalating design (Dose 1–4, equivalent to 1.9, 11, 67, and 410 μg/kg per min) followed by 120 min of washout (WO 10–120) demonstrated baroreflex-compensated hypotension in response to compound 2. The dotted and solid lines represent an untreated time-match control rat in the same setting. Data are Mean±SEM for the last 5 min at each dose level.

Mentions: In the swivel study, we aimed to investigate the effects on blood pressure and HR in conscious rats, and generate data suitable for PK–PD modelling by infusing compound 2 intravenously as a four-step design (Dose 1–4, equivalent to 1.9, 11, 67 and 410 μg/kg per min for 15 min at each step). The main findings of the study were tachycardia and hypotension already at low plasma concentrations of compound 2, but also fatigue and a significant reduction of core body temperature at the highest dose. HR was statistically increased from 381 ± 21 to 472 ± 33 bpm at dose 2 (P < 0.001), whereas the blood pressure effects were significantly lower from baseline at dose 3 (114 ± 9 vs. 98 ± 9 mmHg, respectively, P = 0.006). Neither blood pressure, nor HR was returned to normal 2 h postdosing of compound 2 (100 ± 7 mmHg and 489 ± 41 bpm, P < 0.01). Figure8 demonstrates the MAP and HR time-course for the treated rats versus one time-matched control rat.


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 comes before hypotension as the plasma concentration of compound 2 increases. Blood pressure (white bars) and heart rate (black bars) in 6 conscious rats during a 4-step intravenous escalating design (Dose 1–4, equivalent to 1.9, 11, 67, and 410 μg/kg per min) followed by 120 min of washout (WO 10–120) demonstrated baroreflex-compensated hypotension in response to compound 2. The dotted and solid lines represent an untreated time-match control rat in the same setting. Data are Mean±SEM for the last 5 min at each dose level.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig08: Tachycardia comes before hypotension as the plasma concentration of compound 2 increases. Blood pressure (white bars) and heart rate (black bars) in 6 conscious rats during a 4-step intravenous escalating design (Dose 1–4, equivalent to 1.9, 11, 67, and 410 μg/kg per min) followed by 120 min of washout (WO 10–120) demonstrated baroreflex-compensated hypotension in response to compound 2. The dotted and solid lines represent an untreated time-match control rat in the same setting. Data are Mean±SEM for the last 5 min at each dose level.
Mentions: In the swivel study, we aimed to investigate the effects on blood pressure and HR in conscious rats, and generate data suitable for PK–PD modelling by infusing compound 2 intravenously as a four-step design (Dose 1–4, equivalent to 1.9, 11, 67 and 410 μg/kg per min for 15 min at each step). The main findings of the study were tachycardia and hypotension already at low plasma concentrations of compound 2, but also fatigue and a significant reduction of core body temperature at the highest dose. HR was statistically increased from 381 ± 21 to 472 ± 33 bpm at dose 2 (P < 0.001), whereas the blood pressure effects were significantly lower from baseline at dose 3 (114 ± 9 vs. 98 ± 9 mmHg, respectively, P = 0.006). Neither blood pressure, nor HR was returned to normal 2 h postdosing of compound 2 (100 ± 7 mmHg and 489 ± 41 bpm, P < 0.01). Figure8 demonstrates the MAP and HR time-course for the treated rats versus one time-matched control rat.

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