1. The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD.
- Author
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Mete A, Bowers K, Bull RJ, Coope H, Donald DK, Escott KJ, Ford R, Grime K, Mather A, Ray NC, and Russell V
- Subjects
- Administration, Inhalation, Animals, Bronchoconstriction drug effects, Cycloheptanes pharmacokinetics, Disease Models, Animal, Guinea Pigs, Humans, Molecular Structure, Muscarinic Antagonists pharmacokinetics, Receptors, Muscarinic chemistry, Receptors, Muscarinic metabolism, Cycloheptanes chemistry, Cycloheptanes pharmacology, Muscarinic Antagonists administration & dosage, Muscarinic Antagonists chemistry, Pulmonary Disease, Chronic Obstructive drug therapy
- 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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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