A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of beta2-adrenoceptor agonists as inhaled long-acting bronchodilators.

Research paper by David D Beattie, Michelle M Bradley, Andrew A Brearley, Steven J SJ Charlton, Bernard M BM Cuenoud, Robin A RA Fairhurst, Peter P Gedeck, Martin M Gosling, Diana D Janus, Darryl D Jones, Christine C Lewis, Clive C McCarthy, Helen H Oakman, Rowan R Stringer, Roger J RJ Taylor, et al.

Indexed on: 27 Jul '10Published on: 27 Jul '10Published in: Bioorganic & Medicinal Chemistry Letters


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.