title: A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of beta2-adrenoceptor agonists as inhaled long-acting bronchodilators.
abstract: The chiral synthesis of a 4-hydroxybenzothiazolone based series of beta(2)-adrenoceptor agonists is described. Using this methodology a library of N-substituted analogues were prepared for the rapid identification of leads with the potential to be fast onset and long-acting inhaled bronchodilators with improved therapeutic margins. The design of the library to achieve the targeted profile was based upon lipophilicity and metabolism based hypotheses. This approach identified beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively.
authors.affiliation: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Horsham, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Beattie
authors.forename: Michelle
authors.initials: M
authors.lastname: Bradley
authors.forename: Andrew
authors.initials: A
authors.lastname: Brearley
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
authors.forename: Bernard M
authors.initials: BM
authors.lastname: Cuenoud
authors.forename: Robin A
authors.initials: RA
authors.lastname: Fairhurst
authors.forename: Peter
authors.initials: P
authors.lastname: Gedeck
authors.forename: Martin
authors.initials: M
authors.lastname: Gosling
authors.forename: Diana
authors.initials: D
authors.lastname: Janus
authors.forename: Darryl
authors.initials: D
authors.lastname: Jones
authors.forename: Christine
authors.initials: C
authors.lastname: Lewis
authors.forename: Clive
authors.initials: C
authors.lastname: McCarthy
authors.forename: Helen
authors.initials: H
authors.lastname: Oakman
authors.forename: Rowan
authors.initials: R
authors.lastname: Stringer
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Taylor
authors.forename: Andrew
authors.initials: A
authors.lastname: Tuffnell
mesh_terms: D000280:Administration, Inhalation; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D001993:Bronchodilator Agents; D013844:Thiazoles