title: Discovery of AZD3199, An Inhaled Ultralong Acting β2 Receptor Agonist with Rapid Onset of Action.
abstract: A series of dibasic des-hydroxy β2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human β-adrenoreceptors demonstrated a series of highly potent and selective β2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled β2 receptor agonist with rapid onset of action.
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stocks
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Lilian
authors.initials: L
authors.lastname: Alcaraz
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bailey
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Roger
authors.initials: R
authors.lastname: Bonnert
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Elaine
authors.initials: E
authors.lastname: Cadogan
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Jadeen
authors.initials: J
authors.lastname: Christie
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: John
authors.initials: J
authors.lastname: Dixon
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Stephen
authors.initials: S
authors.lastname: Connolly
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cook
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Adrian
authors.initials: A
authors.lastname: Fisher
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Alice
authors.initials: A
authors.lastname: Flaherty
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Alexander
authors.initials: A
authors.lastname: Humphries
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Anthony
authors.initials: A
authors.lastname: Ingall
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Stephen
authors.initials: S
authors.lastname: Jordan
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Mandy
authors.initials: M
authors.lastname: Lawson
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Alex
authors.initials: A
authors.lastname: Mullen
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Nicholls
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Stuart
authors.initials: S
authors.lastname: Paine
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Garry
authors.initials: G
authors.lastname: Pairaudeau
authors.affiliation: Department of Medicinal Chemistry, Department of Bioscience, and Department of Physical and Metabolic Sciences, AstraZeneca R&D Charnwood , Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K.
authors.forename: Alan
authors.initials: A
authors.lastname: Young
keywords: AZD3199; COPD; adrenoreceptor agonist; asthma; inhaled; uLABA; β2 receptor agonist