Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD

• Published in: Bioorganic & medicinal chemistry letters 2014-07, Vol.24 (13), p.2871-2876
• Main Authors: McKinnell, R Murray, Klein, Uwe, Linsell, Martin S, Moran, Edmund J, Nodwell, Matthew B, Pfeiffer, Juergen W, Thomas, G Roger, Yu, Cecile, Jacobsen, John R
• Format: Article
• Language: English
• Subjects: Adrenergic beta-2 Receptor Agonists - chemical synthesis; Adrenergic beta-2 Receptor Agonists - chemistry; Adrenergic beta-2 Receptor Agonists - pharmacology; Animals; Asthma - drug therapy; Asthma - metabolism; Cell Line; Diphenylamine - analogs & derivatives; Diphenylamine - chemical synthesis; Diphenylamine - chemistry; Diphenylamine - pharmacology; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Discovery; Guinea Pigs; Humans; Molecular Structure; Pulmonary Disease, Chronic Obstructive - drug therapy; Pulmonary Disease, Chronic Obstructive - metabolism; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; Rats; Receptors, Adrenergic, beta-2 - metabolism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.04.095

A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing.