title: The discovery of a selective and potent A2a agonist with extended lung retention.
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.
authors.affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Annika B M
authors.initials: AB
authors.lastname: Åstrand
authors.affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Lamm Bergström
authors.affiliation: Drug Safety & Metabolism, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Börjesson
authors.affiliation: Drug Safety & Metabolism, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Söderdahl
authors.affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Wingren
authors.affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Anne-Helene
authors.initials: AH
authors.lastname: Jansson
authors.affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Amir
authors.initials: A
authors.lastname: Smailagic
authors.affiliation: Drug Safety & Metabolism, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Johansson
authors.affiliation: AstraZeneca R&D Lund SE-221 87, Lund, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Bladh
authors.affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Igor
authors.initials: I
authors.lastname: Shamovsky
authors.affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Tunek
authors.affiliation: RIA iMed, AstraZeneca R&D Mölndal SE-431 59, Mölndal, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Drmota
keywords: A2a; Adenosine receptor; blood pressure; heart rate; inflammation; lung retention; pharmacokinetic-pharmacodynamic; therapeutic window