title: A multivalent approach to the discovery of long-acting β(2)-adrenoceptor agonists for the treatment of asthma and COPD.
abstract: A multivalent approach was applied to the design of long-acting inhaled β(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β(2)-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C(2)-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection.
authors.affiliation: Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA. jjacobsen@theravance.com
authors.forename: John R
authors.initials: JR
authors.lastname: Jacobsen
authors.forename: Seok Ki
authors.initials: SK
authors.lastname: Choi
authors.forename: Jesse
authors.initials: J
authors.lastname: Combs
authors.forename: Eric J L
authors.initials: EJ
authors.lastname: Fournier
authors.forename: Uwe
authors.initials: U
authors.lastname: Klein
authors.forename: Juergen W
authors.initials: JW
authors.lastname: Pfeiffer
authors.forename: G Roger
authors.initials: GR
authors.lastname: Thomas
authors.forename: Cecile
authors.initials: C
authors.lastname: Yu
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Moran
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D002460:Cell Line; D055808:Drug Discovery; D006168:Guinea Pigs; D006801:Humans; D015394:Molecular Structure; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D013237:Stereoisomerism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018927:Anti-Asthmatic Agents