Philipp Lustenberger

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 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.

Studies towards topical selective β2-adrenoceptor agonists with a long duration of action

Beta2-adrenoceptor agonists with basic and acidic groups attached via an alkyl linker to the phenyl ethanolamine core were prepared and investigated in vitro and in vivo. The compounds exhibited a high potency in a functional cellular assay and a bronchoprotective effect in a guinea pig model which lasted over the complete study period of 5h.

Design, synthesis and evaluation of MCH receptor 1 antagonists—Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414

Despite recent approvals of anti-obesity drugs there is still a high therapeutic need for alternative options with higher efficacy in humans. As part of our MCH-R1 antagonist program for the treatment of obesity, a series of biphenylacetamide HTS hits was evaluated. Several issues of the initial lead structures had to be resolved, such as potency, selectivity over related GPCRs and P-gp efflux limiting brain exposure in this series. We could demonstrate that all parameters can be significantly improved by structural modifications resulting in BI 414 as a potent and orally available MCH-R1 antagonist tool compound with acceptable in vivo efficacy in an animal model of obesity.