title: Third-generation long-acting β₂-adrenoceptor agonists: medicinal chemistry strategies employed in the identification of once-daily inhaled β₂-adrenoceptor agonists.
abstract: Inhaled long-acting β(2)-adrenoceptor agonists (LABAs) are highly effective bronchodilators in the treatment of asthma and chronic obstructive pulmonary disease. There is significant interest in the development of third-generation compounds that improve upon the marketed twice-daily LABAs salmeterol and formoterol. A principal advantage sought from the next generation is duration of action that supports once-daily dosing, although improved efficacy, faster onset, and increased therapeutic index are also frequently cited as objectives. Recent publications detailing medicinal chemistry programs directed at the discovery of third-generation LABAs illustrate a wide variety of strategies that have been successfully employed towards these goals. Some recent scientific advances in the understanding of inhaled bronchodilators are discussed and the reported medicinal chemistry strategies are reviewed in the context of these advances.
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
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2