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Bioorg Med Chem Lett. 2014 Jul 1;24(13):2871-6. doi: 10.1016/j.bmcl.2014.04.095. Epub 2014 May 4.

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

Author information

1
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA. Electronic address: mmckinnell@theravance.com.
2
Theravance, Inc., 901 Gateway Blvd., South San Francisco, CA 94080, USA.

Abstract

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.

KEYWORDS:

Bronchodilator; Inhaled; LABA; Multivalent approach; β(2)-Adrenoceptor agonist

PMID:
24835980
DOI:
10.1016/j.bmcl.2014.04.095
[Indexed for MEDLINE]

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