Toward lung-selective β2-adrenergic bronchodilator prodrugs

The ultimate goal in prodrug design would be an inactive site-specific prodrug that delivers active drug only to the target tissue. In this case, the usual strategy of preparing a bioreversible derivative or transport form of a given drug may fail, and more sophisticated approaches would be needed. A number of problems can be identified, but the following three issues should be considered: (1) the metabolic stability of the prodrug during its distribution to the target organ, (2) identification of the uptake mechanism(s) used by the target tissue, and (3) bioconversion in the target tissue of prodrug to active drug and its selective accumulation in the target tissue. A number of specific examples are reviewed with the aim of illustrating the different approaches used to achieve lung-selective adrenergic bronchodilator prodrugs.