1055276-52-2Relevant articles and documents
Multivalent design of long-acting β2-adrenoceptor agonists incorporating biarylamines
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.
, p. 2625 - 2630 (2014/06/09)
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.
