Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy.

Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4] oxazin-3-ones as potent agonist of the human b2-adrenoceptor with a high b1/b2-selectivity. A complete reversal of acetylcholine-induced bronchoconstrictionwhich lasted over the whole study period of 5 h 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. Formoterolwhich was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstrictiondid 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. 2010 Elsevier Ltd. All rights reserved. COPD and asthma are characterized by a reduced airflow on expiration and difficulty in breathing. b2-Adrenoceptor agonists are used for the treatment of both conditions due to their bronchodilatory effect mediated by a relaxation of the airway smooth muscles through an increase of cAMP. The availability of once-daily corticosteroids and the once-daily anticholinergictiotropium, a bronchodilator with a different mechanism of action, suggested the development of b2-agonists suitable for a q.d. dosing regiment 1