A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of beta2-adrenoceptor agonists as inhaled long-acting bronchodilators.
Beattie D, Bradley M, Brearley A, Charlton SJ, Cuenoud BM, Fairhurst RA, Gedeck P, Gosling M, Janus D, Jones D, Lewis C, McCarthy C, Oakman H, Stringer R, Taylor RJ, Tuffnell A.
The chiral synthesis of a 4-hydroxybenzothiazolone based series of beta(2)-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 beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively.