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Bioorg Med Chem Lett. 2014 Jun 15;24(12):2625-30. doi: 10.1016/j.bmcl.2014.04.069. Epub 2014 Apr 26.

Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines.

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Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA. Electronic address:
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.


A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs.


Bronchodilator; Inhaled; LABA; Multivalent approach; β(2)-Adrenoceptor agonist

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