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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
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The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1- hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting ß2-adrenoceptor agonist
The optimisation of two series of 4-hydroxybenzothiazolone derived ß2-adrenoceptor agonists, bearing a-substituted cyclopentyl and ß-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the a-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting ß2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project. © 2014 Elsevier Ltd. All rights reserved