Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD.

Abstract A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β 2 -agonists. Addition of amine moieties to the neutral secondary binding group of an existing β 2 -agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β 2 -agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β 2 -agonist with potential for once-daily dosing.