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

• Published in: Bioorganic & medicinal chemistry letters 2014-06, Vol.24 (12), p.2625-2630
• Main Authors: Jacobsen, John R, Aggen, James B, Church, Timothy J, Klein, Uwe, Pfeiffer, Juergen W, Pulido-Rios, Teresa M, Thomas, G Roger, Yu, Cecile, Moran, Edmund J
• Format: Article
• Language: English
• Subjects: Adrenergic beta-2 Receptor Agonists - chemical synthesis; Adrenergic beta-2 Receptor Agonists - chemistry; Amines - chemical synthesis; Amines - chemistry; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Guinea Pigs; Humans; Lung Diseases, Obstructive - drug therapy; Molecular Structure
• ISSN: 1464-3405
• DOI: 10.1016/j.bmcl.2014.04.069

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.