title: The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist.
abstract: The optimisation of two series of 4-hydroxybenzothiazolone derived β2-adrenoceptor agonists, bearing α-substituted cyclopentyl and β-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting β2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Nicola
authors: N
authors: Arnold
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: David
authors: D
authors: Beattie
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Michelle
authors: M
authors: Bradley
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Andrew
authors: A
authors: Brearley
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Lyndon
authors: L
authors: Brown
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Steven J
authors: SJ
authors: Charlton
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland. Electronic address: robin.fairhurst@novartis.com.
authors: Robin A
authors: RA
authors: Fairhurst
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: David
authors: D
authors: Farr
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: John
authors: J
authors: Fozard
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Joe
authors: J
authors: Fullerton
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Martin
authors: M
authors: Gosling
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Julia
authors: J
authors: Hatto
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Diana
authors: D
authors: Janus
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Darryl
authors: D
authors: Jones
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Lynne
authors: L
authors: Jordan
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Christine
authors: C
authors: Lewis
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Janet
authors: J
authors: Maas
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Clive
authors: C
authors: McCarthy
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Mark
authors: M
authors: Mercer
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Helen
authors: H
authors: Oakman
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Neil
authors: N
authors: Press
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Rachel
authors: R
authors: Profit
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Friedrich
authors: F
authors: Schuerch
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: David
authors: D
authors: Sykes
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Roger J
authors: RJ
authors: Taylor
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Alexandre
authors: A
authors: Trifilieff
authors: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom; Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors: Andrew
authors: A
authors: Tuffnell
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D015394:Molecular Structure; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
chemical_list: C000595934:7-(2-(2-benzyloxycyclopentylamino)-1-hydroxyethyl)-4-hydroxybenzothiazolone; D058666:Adrenergic beta-2 Receptor Agonists; D052160:Benzothiazoles; D018343:Receptors, Adrenergic, beta-2
keywords: Bronchodilator; Chronic obstructive pulmonary disease; β(2)-Adrenoceptor agonist