A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of ß2-adrenoceptor agonists as inhaled long-acting bronchodilators

The chiral synthesis of a 4-hydroxybenzothiazolone based series of ß2-adrenoceptor agonists is described. Using this methodology a library of N-substituted analogues were prepared for the rapid identification of leads with the potential to be fast onset and long-acting inhaled bronchodilators with improved therapeutic margins. The design of the library to achieve the targeted profile was based upon lipophilicity and metabolism based hypotheses. This approach identified ß-phenethyl, a-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively. © 2010 Elsevier Ltd. All rights reserved.