A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of β 2-adrenoceptor agonists as inhaled long-acting bronchodilators

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 17; pp. 5302 - 5307
• Main Authors: Beattie, David, Bradley, Michelle, Brearley, Andrew, Charlton, Steven J., Cuenoud, Bernard M., Fairhurst, Robin A., Gedeck, Peter, Gosling, Martin, Janus, Diana, Jones, Darryl, Lewis, Christine, McCarthy, Clive, Oakman, Helen, Stringer, Rowan, Taylor, Roger J., Tuffnell, Andrew
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 2010
• Subjects: 4-Hydroxybenzothiazolone; Bronchodilator; β 2-Adrenoceptor agonist; β 2-Adrenoceptor agonist; Bronchodilator; 4-Hydroxybenzothiazolone
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.06.136

The chiral synthesis of a 4-hydroxybenzothiazolone based series of β 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 β-phenethyl, α-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively.