Limits...
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

Numbering of A2a agonists. Positions C2 and N6 (highlighted) were subjected to the optimization.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492750&req=5

fig02: Numbering of A2a agonists. Positions C2 and N6 (highlighted) were subjected to the optimization.

Mentions: The medicinal chemistry synthetic optimization focused on the position C2 and N6 (Fig.2) with the aim to discover a compound with high A2a potency, high selectivity, low lipophilicity (logD), and high solubility. The 1-ethylpropyl substituents on N6 (compound 1 and 2, Fig.3) gave good A2a selectivity over A1, A2b, and A3 and were found to be optimal for potency whilst keeping the logD low and solubility high (Tables3). Introduction of a positive charge in compound 2 via methylation of the pyridine in the position 2 of compound 1 increased rat lung t½ to 53 h, and additionally such modification did not compromise the other required properties (Fig.3; Tables3). Compound 2 in comparison with UK-432,097 has low logD (less than −1), high solubility (>1000 μmol/L), low plasma protein binding, and rat lung t½ increased by 13-fold (Table1). The in vitro human A2a potency was 1.4 nmol/L and selectivity over the other human adenosine receptors was >1000-fold for compound 2 (Tables2 and 3). Furthermore, compound 2 showed similar potency in two biological effect assays that is, inhibition of LPS stimulated TNFα release in human PBMC (EC50 = 0.5 nmol/L) and rat splenocytes (EC50 = 0.6 nmol/L) confirming its anti-inflammatory effect via A2a activation in a native cellular system (Tables2 and 3). Selectivity of compound 2 was tested across 98 targets in binding assays (www.ricerca.com). The only identified significant hits (i.e., >50% effect at 10 μmol/L of compound 2) were A2a (∼100%) and A3 (∼84%) data on AstraZeneca file.


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)

Numbering of A2a agonists. Positions C2 and N6 (highlighted) were subjected to the optimization.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: Numbering of A2a agonists. Positions C2 and N6 (highlighted) were subjected to the optimization.
Mentions: The medicinal chemistry synthetic optimization focused on the position C2 and N6 (Fig.2) with the aim to discover a compound with high A2a potency, high selectivity, low lipophilicity (logD), and high solubility. The 1-ethylpropyl substituents on N6 (compound 1 and 2, Fig.3) gave good A2a selectivity over A1, A2b, and A3 and were found to be optimal for potency whilst keeping the logD low and solubility high (Tables3). Introduction of a positive charge in compound 2 via methylation of the pyridine in the position 2 of compound 1 increased rat lung t½ to 53 h, and additionally such modification did not compromise the other required properties (Fig.3; Tables3). Compound 2 in comparison with UK-432,097 has low logD (less than −1), high solubility (>1000 μmol/L), low plasma protein binding, and rat lung t½ increased by 13-fold (Table1). The in vitro human A2a potency was 1.4 nmol/L and selectivity over the other human adenosine receptors was >1000-fold for compound 2 (Tables2 and 3). Furthermore, compound 2 showed similar potency in two biological effect assays that is, inhibition of LPS stimulated TNFα release in human PBMC (EC50 = 0.5 nmol/L) and rat splenocytes (EC50 = 0.6 nmol/L) confirming its anti-inflammatory effect via A2a activation in a native cellular system (Tables2 and 3). Selectivity of compound 2 was tested across 98 targets in binding assays (www.ricerca.com). The only identified significant hits (i.e., >50% effect at 10 μmol/L of compound 2) were A2a (∼100%) and A3 (∼84%) data on AstraZeneca file.

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