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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

Binding mode of compound 2 in the X-ray structure of human A2a in the agonistic conformation. Residues critical for potency and selectivity are indicated. The urea fragment of the C2-side chain is H-bonded to E-169 and Y-271. The terminal positively charged guanidinium moiety is exposed to the extracellular environment and squeezed between residues L167 and L267. H-bonds are shown by red dotted lines. Carbon atoms of compound 2 are shown in light green. Nonpolar hydrogens are not shown for clarity.
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fig13: Binding mode of compound 2 in the X-ray structure of human A2a in the agonistic conformation. Residues critical for potency and selectivity are indicated. The urea fragment of the C2-side chain is H-bonded to E-169 and Y-271. The terminal positively charged guanidinium moiety is exposed to the extracellular environment and squeezed between residues L167 and L267. H-bonds are shown by red dotted lines. Carbon atoms of compound 2 are shown in light green. Nonpolar hydrogens are not shown for clarity.

Mentions: There is scarce public information on molecular drivers to achieve optimal lung retention. It has previously been shown that basic and dibasic compounds may in some cases provide good retention in the lung (Cooper et al. 2012), albeit this does not apply in all cases and is difficult to predict. Compound 2 was designed from compound 1 by methylating the pyridine giving a highly soluble compound with extended rat lung t½, increased potency, maintained selectivity profile, very low logD and low plasma protein binding (Table1). Figure13 illustrates the binding mode of compound 2 docked into the X-ray A2a crystallographic structure in the agonistic conformation (Lebon et al. 2011; Deflorian et al. 2012). The positively charged pyridinium ring with the directly coupled urea creates a cationic conjugated system that forms a strong ionic H-bond to E-169 and an additional H-bond to Y-271. Therefore, the C2 side chain in compound 2 underlines dramatic improvement of rat lung retention together with gain of new interactions between A2a receptor and compound 2.


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)

Binding mode of compound 2 in the X-ray structure of human A2a in the agonistic conformation. Residues critical for potency and selectivity are indicated. The urea fragment of the C2-side chain is H-bonded to E-169 and Y-271. The terminal positively charged guanidinium moiety is exposed to the extracellular environment and squeezed between residues L167 and L267. H-bonds are shown by red dotted lines. Carbon atoms of compound 2 are shown in light green. Nonpolar hydrogens are not shown for clarity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig13: Binding mode of compound 2 in the X-ray structure of human A2a in the agonistic conformation. Residues critical for potency and selectivity are indicated. The urea fragment of the C2-side chain is H-bonded to E-169 and Y-271. The terminal positively charged guanidinium moiety is exposed to the extracellular environment and squeezed between residues L167 and L267. H-bonds are shown by red dotted lines. Carbon atoms of compound 2 are shown in light green. Nonpolar hydrogens are not shown for clarity.
Mentions: There is scarce public information on molecular drivers to achieve optimal lung retention. It has previously been shown that basic and dibasic compounds may in some cases provide good retention in the lung (Cooper et al. 2012), albeit this does not apply in all cases and is difficult to predict. Compound 2 was designed from compound 1 by methylating the pyridine giving a highly soluble compound with extended rat lung t½, increased potency, maintained selectivity profile, very low logD and low plasma protein binding (Table1). Figure13 illustrates the binding mode of compound 2 docked into the X-ray A2a crystallographic structure in the agonistic conformation (Lebon et al. 2011; Deflorian et al. 2012). The positively charged pyridinium ring with the directly coupled urea creates a cationic conjugated system that forms a strong ionic H-bond to E-169 and an additional H-bond to Y-271. Therefore, the C2 side chain in compound 2 underlines dramatic improvement of rat lung retention together with gain of new interactions between A2a receptor and compound 2.

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