title: Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines.
abstract: 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.
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA. Electronic address: jjacobsen@theravance.com.
authors.forename: John R
authors.initials: JR
authors.lastname: Jacobsen
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Aggen
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Church
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Klein
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
authors.forename: Juergen W
authors.initials: JW
authors.lastname: Pfeiffer
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Pulido-Rios
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
authors.forename: G Roger
authors.initials: GR
authors.lastname: Thomas
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
authors.forename: Cecile
authors.initials: C
authors.lastname: Yu
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Moran
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D008173:Lung Diseases, Obstructive / Q000188:drug therapy; D015394:Molecular Structure
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000588:Amines
keywords: Bronchodilator; Inhaled; LABA; Multivalent approach; β(2)-Adrenoceptor agonist