Designing inhaled small molecule drugs for severe respiratory diseases: an overview of the challenges and opportunities.

Introduction: Inhaled drugs offer advantages for the treatment of respiratory diseases over oral drugs by delivering the drug directly to the lung, thus improving the therapeutic index. There is an unmet medical need for novel therapies for lung diseases, exacerbated by a multitude of challenges for the design of inhaled small molecule drugs.

Areas covered: The authors review the challenges and opportunities for the design of inhaled drugs for respiratory diseases with a focus on new target discovery, medicinal chemistry, and pharmacokinetic, pharmacodynamic, and toxicological evaluation of drug candidates.

Expert opinion: Inhaled drug discovery is facing multiple unique challenges. Novel biological targets are scarce, as is the guidance for medicinal chemistry teams to design compounds with inhalation-compatible features. It is exceedingly difficult to establish a PK/PD relationship given the complexity of pulmonary PK and the impact of physical properties of the drug substance on PK. PK, PD and toxicology studies are technically challenging and require large amounts of drug substance. Despite the current challenges, the authors foresee that the design of inhaled drugs will be facilitated in the future by our increasing understanding of pathobiology, emerging medicinal chemistry guidelines, advances in drug formulation, PBPK models, and in vitro toxicology assays.