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

Bioorganic & Medicinal Chemistry Letters
David BeattieAndrew Tuffnell

Abstract

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.

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Citations

Jan 17, 2016·Molecular Pharmacology·Elizabeth M RosethorneSteven J Charlton
Dec 19, 2019·Pharmacological Reviews·M G MateraM Cazzola
Jan 15, 2015·Journal of Medicinal Chemistry·Paolo Montuschi, Giovanni Ciabattoni
Jun 10, 2011·Bioorganic & Medicinal Chemistry Letters·Michael J StocksAlan Young

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