Bronchodilators and anti-inflammatory drugs have been effectively used in the treatment of respiratory disease for decades.  Delivered orally, members of these classes generally have dose-limiting effects mediated systemically.  Consequently, many respiratory drugs have been developed for topical delivery to the lung by oral inhalation in order to achieve efficacious concentrations at the desired site of action while limiting drug levels in the systemic circulation.  An inhaled medicine must be efficiently delivered to the lung, reach its pharmacological target, maintain activity over the dosing interval and be safely and rapidly cleared from the body.  Understanding of how physicochemical properties and the in vitro biological profiles of compounds can impact these parameters is still at an early stage but is growing rapidly.  Examples of successful inhalation medicines highlight some very different strategies that have addressed the challenges posed by different chemical spaces as well as different target classes.  Our discovery efforts in the field of bronchodilators have demonstrated the potential for very different properties to provide compounds with the potential for potent once-daily dosing.  The �2-adrenoceptor agonist milveterol (TD-3327) was selected for development based on functional potency, suitability for inhalation formulation and duration of action in a guinea pig model of bronchoprotection.  In seeking a second development candidate, we identified a chemically differentiated backup (TD-5471) with markedly different physicochemical properties and profile in vitro.  This may reflect different mechanisms driving potency and duration of action in vivo and supports the potential for multiple and quite different solutions to challenges in inhaled drug discovery.

Medicinal chemistry design for inhaled medicines: Application to long-acting bronchodilators

247th National Meeting (2014)

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