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Biberach an der Riß, Germany

Bouyssou T.,BI Pharma GmbH and Co. KG | Casarosa P.,BI Pharma GmbH and Co. KG | Naline E.,University of Versailles | Pestel S.,BI Pharma GmbH and Co. KG | And 3 more authors.
Journal of Pharmacology and Experimental Therapeutics

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 β2-adrenoceptor (hβ2-AR) agonist, was compared with marketed drugs, such as salmeterol and formoterol. In vitro, olodaterol showed a potent, nearly full agonistic response at the hβ2-AR (EC50 = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (219- and 1622-fold against the hβ1- and hβ3-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 β2-AR agonist has the profile for once-daily dosing in humans concomitant with a fast onset of action and a favorable systemic pharmacodynamic profile. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics. Source

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