Pharmacological Characterization of Olodaterol, a Novel Inhaled β2-Adrenoceptor Agonist exerting a 24-hour long Duration of Action in Preclinical Models

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 β 2 adrenoceptor (hβ 2 -AR) agonist, was compared to marketed drugs, like salmeteroland formoterol. In vitro, olodaterolshowed a potent, nearly full agonistic response at the hβ 2 -AR (EC 50 = 0.1 nM; intrinsic activity= 88% compared to isoprenaline) and a significant selectivity profile (219-fold and 1622-fold towards the hβ 1 - and hβ 3 -ARs, respectively). Similarly, olodaterolwas able to potently reverse contraction induced by different stimuli in isolated human bronchi. In vivo, the bronchoprotective effects of olodateroland formoterolwere assessed in anaesthetized guinea pigs and dogs for up to 24 hours after administration of single doses using the Respimat® Soft Mist TM Inhaler. Heart rate and metabolic parameters (serum potassium, lactateand glucose) were monitored to evaluate systemic pharmacodynamiceffects in the dog model. In both models, olodaterolprovided bronchoprotection over 24 hours. Formoterolapplied at an equally effective dose did not retain efficacy over 24 hours. In both models olodaterolshowed a rapid onsetof actioncomparable to formoterol. Taken together, the preclinical behaviour of olodaterolsuggests that this novel β 2 adrenoceptor agonist has the profile for once-daily dosing in man concomitant with a fast onsetof actionand a favourable systemic pharmacodynamicprofile.