The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD |
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Authors: | Antonio Mete Keith Bowers Richard J Bull Helen Coope David K Donald Katherine J Escott Rhonan Ford Ken Grime Andrew Mather Nicholas C Ray Vince Russell |
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Institution: | 1. Department of Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK;2. Department of Bioscience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK;3. Emerging Innovations Unit, AstraZeneca R&D, Alderley Park, Cheshire SK10 4TF, UK;4. Respiratory, Inflammation & Autoimmunity iMed, AstraZeneca R&D, Molndal, Sweden;5. Argenta Discovery, Flex Meadow, Harlow CM19 5TR, UK;6. Argenta Discovery, Stoke Poges, Slough SL2 4SY, UK |
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Abstract: | A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD.Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models.Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic. |
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Keywords: | COPD Bronchoconstriction Salivation |
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