title: Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models.
abstract: The preclinical pharmacological profile of 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]amino]ethyl]-2H-1,4-benzoxazin-3(4H)-one monohydrochloride (olodaterol, previously known as BI 1744 CL), a novel, enantiomeric pure, inhaled human beta(2)-adrenoceptor (hbeta(2)-AR) agonist, was compared with marketed drugs, such as salmeterol and formoterol. In vitro, olodaterol showed a potent, nearly full agonistic response at the hbeta(2)-AR (EC(50) = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (241- and 2299-fold [corrected] against the hbeta(1)- and hbeta(3)-ARs, respectively). Likewise, olodaterol was able to potently reverse contraction induced by different stimuli in isolated human bronchi. In vivo, antagonistic effects of single doses of olodaterol and formoterol were measured against acetylcholine challenges in anesthetized guinea pigs and dogs for up to 24 h by using the Respimat Soft Mist inhaler. Heart rate and metabolic parameters (serum potassium, lactate, and glucose) were monitored to evaluate systemic pharmacodynamic effects in the dog model. In both models, olodaterol provided bronchoprotection over 24 h. Formoterol applied at an equally effective dose did not retain efficacy over 24 h. In both models olodaterol showed a rapid onset of action comparable with formoterol. Taken together, the preclinical behavior of olodaterol suggests that this novel beta(2)-AR agonist has the profile for once-daily dosing in humans concomitant with a fast onset of action and a favorable systemic pharmacodynamic profile.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. Biberach, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Bouyssou
authors.forename: P
authors.initials: P
authors.lastname: Casarosa
authors.forename: E
authors.initials: E
authors.lastname: Naline
authors.forename: S
authors.initials: S
authors.lastname: Pestel
authors.forename: I
authors.initials: I
authors.lastname: Konetzki
authors.forename: P
authors.initials: P
authors.lastname: Devillier
authors.forename: A
authors.initials: A
authors.lastname: Schnapp
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects*; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D003692:Delayed-Action Preparations; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D011485:Protein Binding; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D013997:Time Factors; D014162:Transfection
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D048588:Benzoxazines; D003692:Delayed-Action Preparations; D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; C549647:olodaterol