A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of β2-adrenoceptor agonists as inhaled long-acting bronchodilators
✍ Scribed by David Beattie; Michelle Bradley; Andrew Brearley; Steven J. Charlton; Bernard M. Cuenoud; Robin A. Fairhurst; Peter Gedeck; Martin Gosling; Diana Janus; Darryl Jones; Christine Lewis; Clive McCarthy; Helen Oakman; Rowan Stringer; Roger J. Taylor; Andrew Tuffnell
- Publisher
- Elsevier Science
- Year
- 2010
- Tongue
- English
- Weight
- 630 KB
- Volume
- 20
- Category
- Article
- ISSN
- 0960-894X
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✦ Synopsis
The chiral synthesis of a 4-hydroxybenzothiazolone based series of b 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 b-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.