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

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Beattie D, Bradley M, Brearley A, Charlton SJ, Cuenoud BM, Fairhurst RA, Gedeck P, Gosling M, Janus D, Jones D, Lewis C, McCarthy C, Oakman H, Stringer R, Taylor RJ, Tuffnell A

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

Bioorg Med Chem Lett. 2010 Sep 1;20(17):5302-7. doi: 10.1016/j.bmcl.2010.06.136. Epub 2010 Jul 1.

PubMed ID

20655218 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Salmeterol	Beta-1 adrenergic receptor	Ki (nM)	801	N/A	N/A	Details