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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

AstraZeneca new compounds. 1: (2S,3S,4R,5R)-N-ethyl-5-[6-(1-ethylpropylamino)-2-[2-(4-pyridylcarbamoylamino)ethylamino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-carboxamide. 2: (2S,3S,4R,5R)-N-ethyl-5-[6-(1-ethylpropylamino)-2-[2-[(1-methylpyridin-1-ium-4-yl)carbamoylamino]ethylamino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-carboxamide. 3: (2S,3S,4R,5R)-5-[6-(2,2-diphenylethylamino)-2-[2-[(1-methylpyridin-1-ium-4-yl)carbamoylamino]ethylamino]purin-9-yl]-N-ethyl-3,4-dihydroxy-tetrahydrofuran-2-carboxamide.
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fig03: AstraZeneca new compounds. 1: (2S,3S,4R,5R)-N-ethyl-5-[6-(1-ethylpropylamino)-2-[2-(4-pyridylcarbamoylamino)ethylamino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-carboxamide. 2: (2S,3S,4R,5R)-N-ethyl-5-[6-(1-ethylpropylamino)-2-[2-[(1-methylpyridin-1-ium-4-yl)carbamoylamino]ethylamino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-carboxamide. 3: (2S,3S,4R,5R)-5-[6-(2,2-diphenylethylamino)-2-[2-[(1-methylpyridin-1-ium-4-yl)carbamoylamino]ethylamino]purin-9-yl]-N-ethyl-3,4-dihydroxy-tetrahydrofuran-2-carboxamide.

Mentions: In this paper, we describe the properties of compound 2 (Fig.3), a highly potent (in vitro EC50 1.4 nmol/L) and selective (>1000-fold over A1, A2b and A3) A2a agonist with proven in vitro/in vivo anti-inflammatory efficacy and high retention in the rat lung after intratracheal (i.t.) instillation (28% of dose remaining in lung after 24 h and a terminal half-life in lung of 53 h). Compound 2 has eminent properties compared to the known clinical candidates (UK-432,097) and tool compound (CGS21680). These favorable properties of compound 2 did not help to separate the anti-inflammatory effect in the lung from systemic vasodilatation. Our thorough work suggested there is limited therapeutic value for inhaled A2a agonists in the treatment of inflammatory lung diseases.


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)

AstraZeneca new compounds. 1: (2S,3S,4R,5R)-N-ethyl-5-[6-(1-ethylpropylamino)-2-[2-(4-pyridylcarbamoylamino)ethylamino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-carboxamide. 2: (2S,3S,4R,5R)-N-ethyl-5-[6-(1-ethylpropylamino)-2-[2-[(1-methylpyridin-1-ium-4-yl)carbamoylamino]ethylamino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-carboxamide. 3: (2S,3S,4R,5R)-5-[6-(2,2-diphenylethylamino)-2-[2-[(1-methylpyridin-1-ium-4-yl)carbamoylamino]ethylamino]purin-9-yl]-N-ethyl-3,4-dihydroxy-tetrahydrofuran-2-carboxamide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: AstraZeneca new compounds. 1: (2S,3S,4R,5R)-N-ethyl-5-[6-(1-ethylpropylamino)-2-[2-(4-pyridylcarbamoylamino)ethylamino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-carboxamide. 2: (2S,3S,4R,5R)-N-ethyl-5-[6-(1-ethylpropylamino)-2-[2-[(1-methylpyridin-1-ium-4-yl)carbamoylamino]ethylamino]purin-9-yl]-3,4-dihydroxy-tetrahydrofuran-2-carboxamide. 3: (2S,3S,4R,5R)-5-[6-(2,2-diphenylethylamino)-2-[2-[(1-methylpyridin-1-ium-4-yl)carbamoylamino]ethylamino]purin-9-yl]-N-ethyl-3,4-dihydroxy-tetrahydrofuran-2-carboxamide.
Mentions: In this paper, we describe the properties of compound 2 (Fig.3), a highly potent (in vitro EC50 1.4 nmol/L) and selective (>1000-fold over A1, A2b and A3) A2a agonist with proven in vitro/in vivo anti-inflammatory efficacy and high retention in the rat lung after intratracheal (i.t.) instillation (28% of dose remaining in lung after 24 h and a terminal half-life in lung of 53 h). Compound 2 has eminent properties compared to the known clinical candidates (UK-432,097) and tool compound (CGS21680). These favorable properties of compound 2 did not help to separate the anti-inflammatory effect in the lung from systemic vasodilatation. Our thorough work suggested there is limited therapeutic value for inhaled A2a agonists in the treatment of inflammatory lung diseases.

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