Progress in the Development of Inhaled, Long-Acting β2-Adrenoceptor Agonists

Publisher Summary Long acting β 2 -adrenoceptor agonists are a highly precedented drug class used for the treatment of asthma and chronic obstructive pulmonary disease (COPD). There are currently two marketed long acting β 2 -adrenoceptor agonists—salmeterol 1 and formoterol 2—neither of which provides a once daily dosing regimen. This chapter discusses various β 2 -adrenoceptor agonist head groups—including 8-hydroxycarbostyril, formamides, and saligenins—employed by researchers and discusses the potential development of dual pharmacology agents. The 8-hydroxycarbostyril moiety is known to have a high affinity for the β 2 -adrenoceptor and has been postulated to give potential slow offset properties to ligands to drive the duration of action. A recently published patent suggests that the maleate salt of indacaterol is highly crystalline, stable, and may be the preferred form of this compound for development and clinical use. The saligenin head group has been used with success to prepare long acting β 2 -adrenoceptor agonists with salmeterol playing a prominent role as a benchmark compound. In this connection, the combination agent Advair™ (salmeterol and fluticasone) is currently in third place globally in terms of sales, thereby demonstrating the success of this approach. The dual pharmacology approach presents a number of potential advantages, including the ease of formulation, simpler pharmacokinetics, and the option of combining the dual agent with a third pharmacology in the inhaler. The most notable effort to combine a second pharmacology with β 2 -adrenoceptor agonism is the development of sibenadet (AR-C68397AA).