title: Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy.
abstract: Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of the human beta2-adrenoceptor with a high beta1/beta2-selectivity. A complete reversal of acetylcholine-induced bronchoconstriction which lasted over the whole study period of 5h was demonstrated for 4p in a guinea pig in vivo model without any signs of cardiovascular effects up to 10-fold above the first dose reaching 100% bronchoprotection. The enantiomerically pure (R)-form of 4p exerted a bronchodilatory efficacy over 24 h in dogs and guinea pigs in the absence of systemic pharmacodynamic effects. Formoterol which was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstriction did not retain efficacy after 24 h. In summary, the preclinical profile of compound (R)-4p (olodaterol, also known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved safety profile.
authors.affiliation: Department of Pulmonary Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bouyssou
authors.forename: Christoph
authors.initials: C
authors.lastname: Hoenke
authors.forename: Klaus
authors.initials: K
authors.lastname: Rudolf
authors.forename: Philipp
authors.initials: P
authors.lastname: Lustenberger
authors.forename: Sabine
authors.initials: S
authors.lastname: Pestel
authors.forename: Peter
authors.initials: P
authors.lastname: Sieger
authors.forename: Ralf
authors.initials: R
authors.lastname: Lotz
authors.forename: Claudia
authors.initials: C
authors.lastname: Heine
authors.forename: Frank H
authors.initials: FH
authors.lastname: Büttner
authors.forename: Andreas
authors.initials: A
authors.lastname: Schnapp
authors.forename: Ingo
authors.initials: I
authors.lastname: Konetzki
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D048588:Benzoxazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000235:genetics; D013237:Stereoisomerism; D016896:Treatment Outcome
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D048588:Benzoxazines; D001993:Bronchodilator Agents; D011994:Recombinant Proteins; C549647:olodaterol