Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD.
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.
['McKinnell|R Murray|RM|', 'Klein|Uwe|U|', 'Linsell|Martin S|MS|', 'Moran|Edmund J|EJ|', 'Nodwell|Matthew B|MB|', 'Pfeiffer|Juergen W|JW|', 'Thomas|G Roger|GR|', 'Yu|Cecile|C|', 'Jacobsen|John R|JR|']
D058666:Adrenergic beta-2 Receptor Agonists D000818:Animals D001249:Asthma D002460:Cell Line D004159:Diphenylamine D004195:Disease Models, Animal D004285:Dogs D004305:Dose-Response Relationship, Drug D055808:Drug Discovery D006168:Guinea Pigs D006801:Humans D015394:Molecular Structure D029424:Pulmonary Disease, Chronic Obstructive D015363:Quinolones D051381:Rats D018343:Receptors, Adrenergic, beta-2 D013329:Structure-Activity Relationship
Multivalent approach Inhaled Bronchodilator LABA β(2)-Adrenoceptor agonist