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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

The heart histopathology and heart weight are altered by compound 2. Rats received a single dose of compound 2 (150 μg/kg) had multifocal myocardial necrotic areas in the heart (A). In the acute damaged areas cardiomyocytes had blurred cellular boundary and eosinophilic cytoplasm. The necrotic areas had negative staining of Troponin T (B). Rats received compound 2 (30 μg/kg) for 4 days had multifocal dense granulation tissue with early scar formation (C). The heart weight was increased in the animals with myocardial lesions. SD, single dose; 4D, dose for 4 days. The bar represents 200 μm.
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fig12: The heart histopathology and heart weight are altered by compound 2. Rats received a single dose of compound 2 (150 μg/kg) had multifocal myocardial necrotic areas in the heart (A). In the acute damaged areas cardiomyocytes had blurred cellular boundary and eosinophilic cytoplasm. The necrotic areas had negative staining of Troponin T (B). Rats received compound 2 (30 μg/kg) for 4 days had multifocal dense granulation tissue with early scar formation (C). The heart weight was increased in the animals with myocardial lesions. SD, single dose; 4D, dose for 4 days. The bar represents 200 μm.

Mentions: One day after receiving the i.t. single dose of compound 2 (150 μg/kg), four of five animals in the group showed multifocal myocardial necrosis (Fig.12A). In these necrotic areas, cardiomyocytes had eosinophilic or pale cytoplasm, patchy loss of cross striations, wavy and blurred cellular boundaries, frequently surrounded by a few inflammatory cells. These areas were randomly distributed in the heart, although more commonly seen in the endocardial regions. In addition, perivascular and/or ventricular edema were also observed in these animals. Immunohistochemistry stain confirmed that Troponin T was negative in the cardiomyocytes of the necrotic regions (Fig.12B).


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)

The heart histopathology and heart weight are altered by compound 2. Rats received a single dose of compound 2 (150 μg/kg) had multifocal myocardial necrotic areas in the heart (A). In the acute damaged areas cardiomyocytes had blurred cellular boundary and eosinophilic cytoplasm. The necrotic areas had negative staining of Troponin T (B). Rats received compound 2 (30 μg/kg) for 4 days had multifocal dense granulation tissue with early scar formation (C). The heart weight was increased in the animals with myocardial lesions. SD, single dose; 4D, dose for 4 days. The bar represents 200 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig12: The heart histopathology and heart weight are altered by compound 2. Rats received a single dose of compound 2 (150 μg/kg) had multifocal myocardial necrotic areas in the heart (A). In the acute damaged areas cardiomyocytes had blurred cellular boundary and eosinophilic cytoplasm. The necrotic areas had negative staining of Troponin T (B). Rats received compound 2 (30 μg/kg) for 4 days had multifocal dense granulation tissue with early scar formation (C). The heart weight was increased in the animals with myocardial lesions. SD, single dose; 4D, dose for 4 days. The bar represents 200 μm.
Mentions: One day after receiving the i.t. single dose of compound 2 (150 μg/kg), four of five animals in the group showed multifocal myocardial necrosis (Fig.12A). In these necrotic areas, cardiomyocytes had eosinophilic or pale cytoplasm, patchy loss of cross striations, wavy and blurred cellular boundaries, frequently surrounded by a few inflammatory cells. These areas were randomly distributed in the heart, although more commonly seen in the endocardial regions. In addition, perivascular and/or ventricular edema were also observed in these animals. Immunohistochemistry stain confirmed that Troponin T was negative in the cardiomyocytes of the necrotic regions (Fig.12B).

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