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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

Different lung retention by inhaled A2a agonists. Percentage of dose remaining in lung tissue following intratracheal administration of CGS21680, UK-432,097 and Compounds 1, 2 and 3 to rats. The dose was 300 μg/kg for CGS21680, 130 μg/kg for UK-432,097 and 17, 17 and 20 μmol/kg for Compounds 1, 2, and 3, respectively. Data are means of n = 2/time point.
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fig05: Different lung retention by inhaled A2a agonists. Percentage of dose remaining in lung tissue following intratracheal administration of CGS21680, UK-432,097 and Compounds 1, 2 and 3 to rats. The dose was 300 μg/kg for CGS21680, 130 μg/kg for UK-432,097 and 17, 17 and 20 μmol/kg for Compounds 1, 2, and 3, respectively. Data are means of n = 2/time point.

Mentions: The PK properties of CGS21680, UK-432,097 and the three in-house compounds (1, 2 and 3) were studied in rats following i.v., oral and intratracheal administration (Table1). The concentration versus time profiles in lung and blood following i.t. dosing are depicted in Figure4, and the percentage of dose remaining in lung tissue derived from the lung concentration data are shown in Figure5. The terminal half-life in lung and lung/blood split, defined as the ratio between the total concentration in lung homogenate 24 h after dose and total blood Cmax after the same dose, were calculated for each compound following i.t. dosing. CGS21680 had minimal lung retention with less than 1% of dose remaining in lung at 4 h after a single dose and a half-life in lung estimated to 1 h, and accordingly the concentration in lung at 24 h was below blood Cmax, that is, no lung/blood split was observed for this compound. UK-432,097 had somewhat higher lung retention with approximately 3% of dose remaining in lung at 6 h, and a lung/blood split of 2.7-fold. Compound 1 had a lung-half life of 6 h, which was dramatically increased to 53 h for its positively charged analog, compound 2, with 28% of dose remaining in lung at 24 h and a lung/blood split of 460-fold. Similar to compound 2, the positively charged compound 3 had good lung retention (lung t½ 80 h and 52% of dose remaining in lung at 24 h, lung/blood split of 1800-fold).


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)

Different lung retention by inhaled A2a agonists. Percentage of dose remaining in lung tissue following intratracheal administration of CGS21680, UK-432,097 and Compounds 1, 2 and 3 to rats. The dose was 300 μg/kg for CGS21680, 130 μg/kg for UK-432,097 and 17, 17 and 20 μmol/kg for Compounds 1, 2, and 3, respectively. Data are means of n = 2/time point.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Different lung retention by inhaled A2a agonists. Percentage of dose remaining in lung tissue following intratracheal administration of CGS21680, UK-432,097 and Compounds 1, 2 and 3 to rats. The dose was 300 μg/kg for CGS21680, 130 μg/kg for UK-432,097 and 17, 17 and 20 μmol/kg for Compounds 1, 2, and 3, respectively. Data are means of n = 2/time point.
Mentions: The PK properties of CGS21680, UK-432,097 and the three in-house compounds (1, 2 and 3) were studied in rats following i.v., oral and intratracheal administration (Table1). The concentration versus time profiles in lung and blood following i.t. dosing are depicted in Figure4, and the percentage of dose remaining in lung tissue derived from the lung concentration data are shown in Figure5. The terminal half-life in lung and lung/blood split, defined as the ratio between the total concentration in lung homogenate 24 h after dose and total blood Cmax after the same dose, were calculated for each compound following i.t. dosing. CGS21680 had minimal lung retention with less than 1% of dose remaining in lung at 4 h after a single dose and a half-life in lung estimated to 1 h, and accordingly the concentration in lung at 24 h was below blood Cmax, that is, no lung/blood split was observed for this compound. UK-432,097 had somewhat higher lung retention with approximately 3% of dose remaining in lung at 6 h, and a lung/blood split of 2.7-fold. Compound 1 had a lung-half life of 6 h, which was dramatically increased to 53 h for its positively charged analog, compound 2, with 28% of dose remaining in lung at 24 h and a lung/blood split of 460-fold. Similar to compound 2, the positively charged compound 3 had good lung retention (lung t½ 80 h and 52% of dose remaining in lung at 24 h, lung/blood split of 1800-fold).

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