Dual Pharmacology

There is ample precedence in the long acting ^-adrenoceptor agonist arena for combination therapy with inhaled corticosteroids (ICS). Notable examples include Advair™, which is the combination of salmeterol and fluticasone, and Symbicort™, which consists of formoterol and budesonide. There is also a proven market for combinations containing M3 antagonists, such as CombiventTM; the latter agent is a mixture of the short-acting ^-adrenoceptor agonist, salbutamol, combined with ipratropium.

An alternative paradigm is to have the two pharmacologies incorporated within a single molecule. The dual pharmacology approach presents a number of potential advantages including 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 ^-adrenoceptor agonism is the development of sibenadet (AR-C68397AA) 32. Attempts were made to combine dopamine D2 agonism with ^-adrenoceptor agonism and this approach was highly encouraging with data being sufficiently attractive to submit sibenadet to

Phase III clinical trials [54,55]. Subsequently, the development of sibenadet was terminated due to the absence of sustained long-term benefits compared to other available treatments. This lack of efficacy was attributed to downregulation of the D2 receptor over the course of the longer Phase III clinical trial [56].

There has been a re-emerging interest of late in designing dual pharmacology agents and in particular, compounds that possess M3 antagonism to complement long-acting ^-adrenoceptor agonism. There have been a number of patent filings around this approach, including the recent disclosure that compound TD-5959 had progressed to preclinical trials [57]. The structure of this compound is currently unknown; however, a recent patent filing describes a crystalline salt form of 33 [58]. This application describes the preparation of the salt and claims that it can be used for the treatment of pulmonary conditions.

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