title: The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD.
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.
authors.affiliation: Department of Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mete
authors.forename: Keith
authors.initials: K
authors.lastname: Bowers
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bull
authors.forename: Helen
authors.initials: H
authors.lastname: Coope
authors.forename: David K
authors.initials: DK
authors.lastname: Donald
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Escott
authors.forename: Rhonan
authors.initials: R
authors.lastname: Ford
authors.forename: Ken
authors.initials: K
authors.lastname: Grime
authors.forename: Andrew
authors.initials: A
authors.lastname: Mather
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Ray
authors.forename: Vince
authors.initials: V
authors.lastname: Russell
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D003508:Cycloheptanes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000378:metabolism
chemical_list: D003508:Cycloheptanes; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic
keywords: Bronchoconstriction; COPD; Muscarinic M(3) antagonist; Salivation