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.
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA. Electronic address: mmckinnell@theravance.com.
R Murray
RM
McKinnell
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
Uwe
U
Klein
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
Martin S
MS
Linsell
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
Edmund J
EJ
Moran
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
Matthew B
MB
Nodwell
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
Juergen W
JW
Pfeiffer
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
G Roger
GR
Thomas
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
Cecile
C
Yu
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.
John R
JR
Jacobsen
D058666:Adrenergic beta-2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; 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 / Q000188:drug therapy* / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D058666:Adrenergic beta-2 Receptor Agonists; D015363:Quinolones; D018343:Receptors, Adrenergic, beta-2; C000595183:TD-4306; D004159:Diphenylamine
Bronchodilator; Inhaled; LABA; Multivalent approach; β(2)-Adrenoceptor agonist